Steve Stiles

The Food and Drug Administration has approved a groundbreaking expanded indication for sacubitril/valsartan (Entresto), making it the first drug in the United States indicated for chronic heart failure not specifically characterized by ejection fraction.

The new labeling, as provided by Novartis, grants physicians a good deal of discretion in prescribing sacubitril/valsartan for patients with HF beyond those with HF and reduced ejection fraction (HFrEF), for which the drug was approved in 2015 primarily on the basis of the PARADIGM-HF trial.

The indication now reads, “to reduce the risk of cardiovascular death and hospitalization for heart failure in adult patients with chronic heart failure. Benefits are most clearly evident in patients with left ventricular ejection fraction (LVEF) below normal.”

Of note, the labeling cautions that “LVEF is a variable measure, so use clinical judgment in deciding whom to treat.”

The expanded indication essentially extends the sacubitril/valsartan option to many patients with HF and preserved LVEF (HFpEF), who in practice are most likely to have an LVEF in the range adjacent to “reduced,” long defined as “preserved” but lately categorized as “mid-range.”

But the FDA did not get so specific. In granting the expanded indication, which Novartis announced Feb. 16 in a press release, the agency accommodated the Dec. 15 majority recommendation of its Cardiovascular and Renal Drugs Advisory Committee that the PARAGON-HF trial “provided sufficient evidence to support” an indication beyond HFrEF.

The nature of the PARAGON-HF trial, along with detailed discussion among committee members after their vote tally, made it clear that the 12-to-1 majority favored an indication that would include clinically appropriate patients with “below normal” LVEF.

PARAGON-HF had assigned more than 4,800 patients whose LVEF was 45% or higher and were in NYHA class 2-4 to receive sacubitril/valsartan or valsartan only. Those taking the combo drug showed a 13% drop in risk for HF hospitalization or cardiovascular deaths over an average of 3 years, which narrowly missed significance (P = .059).

But a subgroup analysis garnered attention for its hint of benefit for patients with “mid-range” LVEF, in this case, below the median of 57%. The finding was supported by a later PARAGON-HF and PARADIGM-HF meta-analysis that pointed to a significant benefit for patients with HFpEF at its lowest LVEF levels, especially in women.

The expanded approval “is a significant advancement, providing a treatment to many patients who were not eligible for treatment before, because their ejection fraction was above the region we normally considered reduced,” Scott Solomon, MD, of Brigham and Women’s Hospital, Boston, said in the Novartis press release. “We can now offer a treatment to a wider range of patients who have an LVEF below normal,” added Dr. Solomon, PARAGON-HF executive committee cochair.

A version of this article first appeared on Medscape.com.

The Food and Drug Administration has approved a groundbreaking expanded indication for sacubitril/valsartan (Entresto), making it the first drug in the United States indicated for chronic heart failure not specifically characterized by ejection fraction.

The new labeling, as provided by Novartis, grants physicians a good deal of discretion in prescribing sacubitril/valsartan for patients with HF beyond those with HF and reduced ejection fraction (HFrEF), for which the drug was approved in 2015 primarily on the basis of the PARADIGM-HF trial.

The indication now reads, “to reduce the risk of cardiovascular death and hospitalization for heart failure in adult patients with chronic heart failure. Benefits are most clearly evident in patients with left ventricular ejection fraction (LVEF) below normal.”

Of note, the labeling cautions that “LVEF is a variable measure, so use clinical judgment in deciding whom to treat.”

The expanded indication essentially extends the sacubitril/valsartan option to many patients with HF and preserved LVEF (HFpEF), who in practice are most likely to have an LVEF in the range adjacent to “reduced,” long defined as “preserved” but lately categorized as “mid-range.”

But the FDA did not get so specific. In granting the expanded indication, which Novartis announced Feb. 16 in a press release, the agency accommodated the Dec. 15 majority recommendation of its Cardiovascular and Renal Drugs Advisory Committee that the PARAGON-HF trial “provided sufficient evidence to support” an indication beyond HFrEF.

The nature of the PARAGON-HF trial, along with detailed discussion among committee members after their vote tally, made it clear that the 12-to-1 majority favored an indication that would include clinically appropriate patients with “below normal” LVEF.

PARAGON-HF had assigned more than 4,800 patients whose LVEF was 45% or higher and were in NYHA class 2-4 to receive sacubitril/valsartan or valsartan only. Those taking the combo drug showed a 13% drop in risk for HF hospitalization or cardiovascular deaths over an average of 3 years, which narrowly missed significance (P = .059).

But a subgroup analysis garnered attention for its hint of benefit for patients with “mid-range” LVEF, in this case, below the median of 57%. The finding was supported by a later PARAGON-HF and PARADIGM-HF meta-analysis that pointed to a significant benefit for patients with HFpEF at its lowest LVEF levels, especially in women.

The expanded approval “is a significant advancement, providing a treatment to many patients who were not eligible for treatment before, because their ejection fraction was above the region we normally considered reduced,” Scott Solomon, MD, of Brigham and Women’s Hospital, Boston, said in the Novartis press release. “We can now offer a treatment to a wider range of patients who have an LVEF below normal,” added Dr. Solomon, PARAGON-HF executive committee cochair.

A version of this article first appeared on Medscape.com.

The Food and Drug Administration has approved a groundbreaking expanded indication for sacubitril/valsartan (Entresto), making it the first drug in the United States indicated for chronic heart failure not specifically characterized by ejection fraction.

The new labeling, as provided by Novartis, grants physicians a good deal of discretion in prescribing sacubitril/valsartan for patients with HF beyond those with HF and reduced ejection fraction (HFrEF), for which the drug was approved in 2015 primarily on the basis of the PARADIGM-HF trial.

The indication now reads, “to reduce the risk of cardiovascular death and hospitalization for heart failure in adult patients with chronic heart failure. Benefits are most clearly evident in patients with left ventricular ejection fraction (LVEF) below normal.”

Of note, the labeling cautions that “LVEF is a variable measure, so use clinical judgment in deciding whom to treat.”

The expanded indication essentially extends the sacubitril/valsartan option to many patients with HF and preserved LVEF (HFpEF), who in practice are most likely to have an LVEF in the range adjacent to “reduced,” long defined as “preserved” but lately categorized as “mid-range.”

But the FDA did not get so specific. In granting the expanded indication, which Novartis announced Feb. 16 in a press release, the agency accommodated the Dec. 15 majority recommendation of its Cardiovascular and Renal Drugs Advisory Committee that the PARAGON-HF trial “provided sufficient evidence to support” an indication beyond HFrEF.

The nature of the PARAGON-HF trial, along with detailed discussion among committee members after their vote tally, made it clear that the 12-to-1 majority favored an indication that would include clinically appropriate patients with “below normal” LVEF.

PARAGON-HF had assigned more than 4,800 patients whose LVEF was 45% or higher and were in NYHA class 2-4 to receive sacubitril/valsartan or valsartan only. Those taking the combo drug showed a 13% drop in risk for HF hospitalization or cardiovascular deaths over an average of 3 years, which narrowly missed significance (P = .059).

But a subgroup analysis garnered attention for its hint of benefit for patients with “mid-range” LVEF, in this case, below the median of 57%. The finding was supported by a later PARAGON-HF and PARADIGM-HF meta-analysis that pointed to a significant benefit for patients with HFpEF at its lowest LVEF levels, especially in women.

The expanded approval “is a significant advancement, providing a treatment to many patients who were not eligible for treatment before, because their ejection fraction was above the region we normally considered reduced,” Scott Solomon, MD, of Brigham and Women’s Hospital, Boston, said in the Novartis press release. “We can now offer a treatment to a wider range of patients who have an LVEF below normal,” added Dr. Solomon, PARAGON-HF executive committee cochair.

A version of this article first appeared on Medscape.com.

The Food and Drug Administration has approved the fully human monoclonal antibody evinacumab-dgnb (Evkeeza, Regeneron Pharmaceuticals) for use on top of other cholesterol-modifying medication in patients aged 12 years and older with homozygous familial hypercholesterolemia (HoFH), the agency and Regeneron have announced.

Evinacumab had received orphan drug designation and underwent priority regulatory review based primarily on the phase 3 ELIPSE trial, presented at a meeting in March 2020 and published in August 2020 in the New England Journal of Medicine (doi: 10.1056/NEJMoa2004215).

In the trial with 65 patients with HoFH on guideline-based lipid-modifying therapy, those who also received evinacumab 15 mg/kg intravenously every 4 weeks showed a nearly 50% drop in LDL cholesterol levels after 24 weeks, compared with patients given a placebo. Only 2% of patients in both groups discontinued therapy because of adverse reactions.

The drug blocks angiopoietin-like 3, itself an inhibitor of lipoprotein lipase and endothelial lipase. It therefore lowers LDL cholesterol levels by mechanisms that don’t directly involve the LDL receptor.

Regeneron estimates that about 1300 people in the United States have the homozygous genetic disorder, which can lead to LDL cholesterol levels of a 1,000 mg/dL or higher, advanced premature atherosclerosis, and extreme risk for cardiovascular events.

The drug’s average wholesale acquisition cost per patient in the United States is expected to be about $450,000 per year, the company said, adding that it has a financial support program to help qualified patients with out-of-pocket costs.

Regeneron’s announcement included a comment from dyslipidemia-therapy expert Daniel J. Rader, MD, University of Pennsylvania, Philadelphia, who called evinacumab “a potentially transformational new treatment for people with HoFH.”

The drug is currently under regulatory review for the same indication in Europe, the company said.

A version of this article first appeared on Medscape.com.

The Food and Drug Administration has approved the fully human monoclonal antibody evinacumab-dgnb (Evkeeza, Regeneron Pharmaceuticals) for use on top of other cholesterol-modifying medication in patients aged 12 years and older with homozygous familial hypercholesterolemia (HoFH), the agency and Regeneron have announced.

Evinacumab had received orphan drug designation and underwent priority regulatory review based primarily on the phase 3 ELIPSE trial, presented at a meeting in March 2020 and published in August 2020 in the New England Journal of Medicine (doi: 10.1056/NEJMoa2004215).

In the trial with 65 patients with HoFH on guideline-based lipid-modifying therapy, those who also received evinacumab 15 mg/kg intravenously every 4 weeks showed a nearly 50% drop in LDL cholesterol levels after 24 weeks, compared with patients given a placebo. Only 2% of patients in both groups discontinued therapy because of adverse reactions.

The drug blocks angiopoietin-like 3, itself an inhibitor of lipoprotein lipase and endothelial lipase. It therefore lowers LDL cholesterol levels by mechanisms that don’t directly involve the LDL receptor.

Regeneron estimates that about 1300 people in the United States have the homozygous genetic disorder, which can lead to LDL cholesterol levels of a 1,000 mg/dL or higher, advanced premature atherosclerosis, and extreme risk for cardiovascular events.

The drug’s average wholesale acquisition cost per patient in the United States is expected to be about $450,000 per year, the company said, adding that it has a financial support program to help qualified patients with out-of-pocket costs.

Regeneron’s announcement included a comment from dyslipidemia-therapy expert Daniel J. Rader, MD, University of Pennsylvania, Philadelphia, who called evinacumab “a potentially transformational new treatment for people with HoFH.”

The drug is currently under regulatory review for the same indication in Europe, the company said.

A version of this article first appeared on Medscape.com.

The Food and Drug Administration has approved the fully human monoclonal antibody evinacumab-dgnb (Evkeeza, Regeneron Pharmaceuticals) for use on top of other cholesterol-modifying medication in patients aged 12 years and older with homozygous familial hypercholesterolemia (HoFH), the agency and Regeneron have announced.

Evinacumab had received orphan drug designation and underwent priority regulatory review based primarily on the phase 3 ELIPSE trial, presented at a meeting in March 2020 and published in August 2020 in the New England Journal of Medicine (doi: 10.1056/NEJMoa2004215).

In the trial with 65 patients with HoFH on guideline-based lipid-modifying therapy, those who also received evinacumab 15 mg/kg intravenously every 4 weeks showed a nearly 50% drop in LDL cholesterol levels after 24 weeks, compared with patients given a placebo. Only 2% of patients in both groups discontinued therapy because of adverse reactions.

The drug blocks angiopoietin-like 3, itself an inhibitor of lipoprotein lipase and endothelial lipase. It therefore lowers LDL cholesterol levels by mechanisms that don’t directly involve the LDL receptor.

Regeneron estimates that about 1300 people in the United States have the homozygous genetic disorder, which can lead to LDL cholesterol levels of a 1,000 mg/dL or higher, advanced premature atherosclerosis, and extreme risk for cardiovascular events.

The drug’s average wholesale acquisition cost per patient in the United States is expected to be about $450,000 per year, the company said, adding that it has a financial support program to help qualified patients with out-of-pocket costs.

Regeneron’s announcement included a comment from dyslipidemia-therapy expert Daniel J. Rader, MD, University of Pennsylvania, Philadelphia, who called evinacumab “a potentially transformational new treatment for people with HoFH.”

The drug is currently under regulatory review for the same indication in Europe, the company said.

A version of this article first appeared on Medscape.com.

Two recent observational studies suggest that myocarditis, at least on cardiac magnetic resonance (CMR) imaging, might be far less common in elite-level athletes recovering from COVID-19 than suggested in influential earlier reports.

AlexLMX/Getty Images

Both new studies documented a rate less than one-quarter as high as those previously reported from smaller cohorts, raising questions about the diagnostic yield of CMR in highly conditioned athletes with recent COVID-19 absent other evidence, such as from biomarker assays or electrocardiography (ECG).

That could have implications for some top-tier university athletics programs that mandate CMR imaging, biomarker assays, and other evaluations for myocarditis on all their players who test positive for SARS-CoV-2 before they can return to play.

The findings collectively point to CMR imaging features that might be a hallmark of an athlete’s heart, characterized by normal myocardial remodeling brought on by elite-level exercise training, which in athletes with recent COVID-19 could be misinterpreted as evidence of myocarditis. That may have thrown off prevalence estimates in the literature, the studies’ investigators speculated.

The two studies were retrospective takes on university athletes who underwent CMR imaging while recovering from COVID-19, who were either asymptomatic or with only mild to moderate symptoms and were generally without ECG or troponin evidence of myocarditis.

One of them showed a less than 2% incidence of myocarditis by CMR among 145 such cases, a low yield for imaging that is “raising doubt regarding its utility to evaluate athletes without a clinical presentation or abnormal ancillary tests to support the diagnosis of myocarditis,” argues a report published Jan. 14 in JAMA Cardiology, with lead author Jitka Starekova, MD, University of Wisconsin – Madison.

“Part of the problem is that occult myocarditis is, at least with other viruses, a risk factor for sudden death in competitive athletes. So you don’t want to let one slip through the cracks,” senior author Scott B. Reeder, MD, PhD, from the same institution, said in an interview.

Whether a policy of routine CMR imaging in elite athletes who test positive for the new coronavirus is better than more selective use driven by symptoms or other screening tests is unknown. But the more pressing issue, Dr. Reeder said, “is if they have a normal electrocardiogram and troponins, do they still need cardiac magnetic resonance imaging?”

The current study, he said, “certainly provides helpful evidence that maybe we don’t need as many.”

The other study, which featured two control groups, saw a similarly low incidence of myocarditis by CMR in athletes with recent COVID-19. One of the control groups included university athletes imaged prior to the advent of SARS-CoV-2 in the university’s region of the country. The other consisted of apparently healthy adult nonathletes.

Armed with two non-COVID-19 cohorts and two athlete cohorts, the researchers found comparable rates of myocarditis by CMR in both the COVID-19 athletes and the healthy athletes. And only 3% of the COVID-19 athletes had the tell-tale CMR signs, notes the report, published Dec. 17 in Circulation, with lead author Daniel E. Clark, MD, MPH, Vanderbilt University Medical Center, Nashville, Tenn.
 

Reassurance and concern

“The incidence is much lower than we feared, and so that’s reassuring,” Clark said in an interview. Still, the athletes with myocarditis by CMR “would have been completely missed by a protocol that did not include cardiac MR, and that’s concerning,” he said. “Both had active myocarditis.”

The study’s two non-COVID-19 control groups – elite athletes in one and nonathletes in the other – allowed them to tease out the potential contribution of athletic myocardial remodeling to CMR features that could be interpreted as scar tissue, which are characterized by late gadolinium enhancement (LGE).

As it turned out, focal regions of LGE located in the right ventricular (RV) septum on the scans were often seen in both athlete cohorts. “This kind of trivial nonischemic fibrosis in the mid RV septal insertion site was common among athletic control subjects. It was seen in 24% of them, which is almost identical to the percentage that we saw in the COVID-19 athletes, 22%,” Dr. Clark said.

The LGE finding, wrote Dr. Clark and coauthors, “may represent remodeling from athletic training, and should not be conflated with myocarditis.”

Of note, the other study saw a comparable incidence of the same or a very similar CMR feature in its athletes; 26% of the Wisconsin COVID-19 athlete cohort showed limited focal LGE in the inferior RV insertion site.

“And you get a little bit in the mid-septum, as well,” Dr. Reeder said. But the sign, in the absence of any corresponding T2 abnormalities, was not judged to represent myocarditis. “We interpreted all of these studies with this potential confounder in mind.”

Conceivably, Dr. Reeder proposed, the earlier studies may have “over-called” the prevalence of myocarditis in their cohorts. “I haven’t seen their images, but it’s possible there could be false-positives.”

It’s noteworthy that the Vanderbilt and Wisconsin reports saw closely similar incidences of the tell-tale CMR sign in all the athlete cohorts whether or not COVID-19 was involved, Aaron L. Baggish, MD, Massachusetts General Hospital, Boston, said in an interview.

“It looks very much like just an unrecognized part of athletic remodeling and isn’t in any way, shape, or form implicated as being a COVID-related issue,” said Dr. Baggish, who directs the cardiovascular performance program at his center and is unaffiliated with either study.

Still, that connection remains unproven given how little is yet known about the prevalence of clinically important myocarditis in milder cases of COVID-19, according to an accompanying editorial from Jonathan H. Kim, MD, MSc.

Although isolated LGE at the interventricular RV insertion site is “more commonly described among masters-level endurance athletes, the clinical significance and prevalence of this finding in youthful athletes is uncertain and should not be assumed to be a normal consequence of intense athletic training in young competitive athletes,” argued Dr. Kim, of Emory University, Atlanta.

There’s probably little about being a young competitive athlete that would render a person any more or less prone to COVID-19 cardiac involvement, Dr. Baggish said. Rather, “I think what we’re seeing, as the studies continue to come out, is that prevalence estimates are getting into the low single digits.”

The estimates are similar to those associated with influenza before the COVID-19 age; about 2% of patients showed cardiac involvement, Dr. Baggish said. “So the degree to which COVID is a special virus from this perspective, I think, is still a topic of some debate.”

The two current studies have limitations and neither is positioned to change practice, he said. “I would say that they are both kind of important, reassuring pieces of an unfinished jigsaw puzzle. But we still don’t know what the picture on the puzzle is.”
 

Routine CMR for positive cases

The University of Wisconsin group looked at all of the institution’s competitive athletes who underwent gadolinium-enhanced CMR imaging and other tests during recovery from COVID-19 from the beginning of the pandemic to the end of November 2020.

The imaging was performed on average about 2 weeks after a first positive SARS-CoV-2 assay result. About one-half and one-fourth of the cohort had experienced mild and moderate symptoms, respectively, and about 17% were asymptomatic; none had been hospitalized.

All CMR scans were reviewed by two experienced radiologists for, among other things, evidence of myocarditis according to modified Lake Louise criteria, the group wrote. Those criteria are based on CMR markers of fibrosis and other characteristics of scarring from myocarditis.

Such evidence was seen in only two members of the cohort, or 1.4%, one with elevated troponins but normal with respect to other biomarkers, and the other negative for all assays. Both were asymptomatic at the time of imaging, the report noted.

The Vanderbilt analysis from Dr. Clark and associates centered on 59 university athletes recently with COVID-19 who underwent CMR imaging along with other tests about 3 weeks after confirmation of SARS-CoV-2 infection. Symptoms had been mild in 78% of the group, and the remainder were asymptomatic.

They were compared with 60 retrospectively identified college athletes and elite-conditioned military personnel who had undergone CMR imaging prior to the advent of COVID-19, and to 27 apparently healthy nonathlete adults in whom CMR had been previously performed to define normal CMR imaging criteria at that center.

The only two post-COVID-19 athletes who met modified Lake Louise criteria for myocarditis showed no abnormalities on ECG or myocardial strain echocardiography, and had normal troponins, the group reported.

The COVID-19 athletes showed increased cardiac chamber volumes and myocardial mass “consistent with athletic remodeling,” compared with the healthy control subjects, the group wrote. But “most standard CMR parameters were similar” between the COVID-19 athletes and the control athletes, consistent with the 22% and 24% rates, respectively, for the finding of focal late LGE isolated to the inferoseptal RV insertion site.

At the end of the day, all published experiences on athletes with recent COVID-19 “are descriptive studies, without any hint of follow-up,” Dr. Baggish noted, so their clinical implications are unknown.

“We need time to sit and watch to see what happens to these individuals,” he said. “And if the answer is nothing, then that’s a very reassuring story. If the answer is that we start to see events, then that’s really important for us to take stock of.”

Dr. Starekova had no disclosures. Dr. Reeder reports that the University of Wisconsin receives research support from GE Healthcare and Bracco Diagnostics; and that he has ownership interests in Calimetrix, Reveal Pharmaceuticals, Cellectar Biosciences, Elucent Medical, and HeartVista; and has received grant support from Bayer Healthcare. Disclosures for the other coauthors are in the report. Dr. Clark and coauthors had no disclosures. Dr. Baggish reported no conflicts. Kim discloses receiving funding from the National Heart, Lung, and Blood Institute; compensation as team cardiologist for the Atlanta Falcons; and research stipends from the Atlanta Track Club.

A version of this article first appeared on Medscape.com.

Two recent observational studies suggest that myocarditis, at least on cardiac magnetic resonance (CMR) imaging, might be far less common in elite-level athletes recovering from COVID-19 than suggested in influential earlier reports.

AlexLMX/Getty Images

Both new studies documented a rate less than one-quarter as high as those previously reported from smaller cohorts, raising questions about the diagnostic yield of CMR in highly conditioned athletes with recent COVID-19 absent other evidence, such as from biomarker assays or electrocardiography (ECG).

That could have implications for some top-tier university athletics programs that mandate CMR imaging, biomarker assays, and other evaluations for myocarditis on all their players who test positive for SARS-CoV-2 before they can return to play.

The findings collectively point to CMR imaging features that might be a hallmark of an athlete’s heart, characterized by normal myocardial remodeling brought on by elite-level exercise training, which in athletes with recent COVID-19 could be misinterpreted as evidence of myocarditis. That may have thrown off prevalence estimates in the literature, the studies’ investigators speculated.

The two studies were retrospective takes on university athletes who underwent CMR imaging while recovering from COVID-19, who were either asymptomatic or with only mild to moderate symptoms and were generally without ECG or troponin evidence of myocarditis.

One of them showed a less than 2% incidence of myocarditis by CMR among 145 such cases, a low yield for imaging that is “raising doubt regarding its utility to evaluate athletes without a clinical presentation or abnormal ancillary tests to support the diagnosis of myocarditis,” argues a report published Jan. 14 in JAMA Cardiology, with lead author Jitka Starekova, MD, University of Wisconsin – Madison.

“Part of the problem is that occult myocarditis is, at least with other viruses, a risk factor for sudden death in competitive athletes. So you don’t want to let one slip through the cracks,” senior author Scott B. Reeder, MD, PhD, from the same institution, said in an interview.

Whether a policy of routine CMR imaging in elite athletes who test positive for the new coronavirus is better than more selective use driven by symptoms or other screening tests is unknown. But the more pressing issue, Dr. Reeder said, “is if they have a normal electrocardiogram and troponins, do they still need cardiac magnetic resonance imaging?”

The current study, he said, “certainly provides helpful evidence that maybe we don’t need as many.”

The other study, which featured two control groups, saw a similarly low incidence of myocarditis by CMR in athletes with recent COVID-19. One of the control groups included university athletes imaged prior to the advent of SARS-CoV-2 in the university’s region of the country. The other consisted of apparently healthy adult nonathletes.

Armed with two non-COVID-19 cohorts and two athlete cohorts, the researchers found comparable rates of myocarditis by CMR in both the COVID-19 athletes and the healthy athletes. And only 3% of the COVID-19 athletes had the tell-tale CMR signs, notes the report, published Dec. 17 in Circulation, with lead author Daniel E. Clark, MD, MPH, Vanderbilt University Medical Center, Nashville, Tenn.
 

Reassurance and concern

“The incidence is much lower than we feared, and so that’s reassuring,” Clark said in an interview. Still, the athletes with myocarditis by CMR “would have been completely missed by a protocol that did not include cardiac MR, and that’s concerning,” he said. “Both had active myocarditis.”

The study’s two non-COVID-19 control groups – elite athletes in one and nonathletes in the other – allowed them to tease out the potential contribution of athletic myocardial remodeling to CMR features that could be interpreted as scar tissue, which are characterized by late gadolinium enhancement (LGE).

As it turned out, focal regions of LGE located in the right ventricular (RV) septum on the scans were often seen in both athlete cohorts. “This kind of trivial nonischemic fibrosis in the mid RV septal insertion site was common among athletic control subjects. It was seen in 24% of them, which is almost identical to the percentage that we saw in the COVID-19 athletes, 22%,” Dr. Clark said.

The LGE finding, wrote Dr. Clark and coauthors, “may represent remodeling from athletic training, and should not be conflated with myocarditis.”

Of note, the other study saw a comparable incidence of the same or a very similar CMR feature in its athletes; 26% of the Wisconsin COVID-19 athlete cohort showed limited focal LGE in the inferior RV insertion site.

“And you get a little bit in the mid-septum, as well,” Dr. Reeder said. But the sign, in the absence of any corresponding T2 abnormalities, was not judged to represent myocarditis. “We interpreted all of these studies with this potential confounder in mind.”

Conceivably, Dr. Reeder proposed, the earlier studies may have “over-called” the prevalence of myocarditis in their cohorts. “I haven’t seen their images, but it’s possible there could be false-positives.”

It’s noteworthy that the Vanderbilt and Wisconsin reports saw closely similar incidences of the tell-tale CMR sign in all the athlete cohorts whether or not COVID-19 was involved, Aaron L. Baggish, MD, Massachusetts General Hospital, Boston, said in an interview.

“It looks very much like just an unrecognized part of athletic remodeling and isn’t in any way, shape, or form implicated as being a COVID-related issue,” said Dr. Baggish, who directs the cardiovascular performance program at his center and is unaffiliated with either study.

Still, that connection remains unproven given how little is yet known about the prevalence of clinically important myocarditis in milder cases of COVID-19, according to an accompanying editorial from Jonathan H. Kim, MD, MSc.

Although isolated LGE at the interventricular RV insertion site is “more commonly described among masters-level endurance athletes, the clinical significance and prevalence of this finding in youthful athletes is uncertain and should not be assumed to be a normal consequence of intense athletic training in young competitive athletes,” argued Dr. Kim, of Emory University, Atlanta.

There’s probably little about being a young competitive athlete that would render a person any more or less prone to COVID-19 cardiac involvement, Dr. Baggish said. Rather, “I think what we’re seeing, as the studies continue to come out, is that prevalence estimates are getting into the low single digits.”

The estimates are similar to those associated with influenza before the COVID-19 age; about 2% of patients showed cardiac involvement, Dr. Baggish said. “So the degree to which COVID is a special virus from this perspective, I think, is still a topic of some debate.”

The two current studies have limitations and neither is positioned to change practice, he said. “I would say that they are both kind of important, reassuring pieces of an unfinished jigsaw puzzle. But we still don’t know what the picture on the puzzle is.”
 

Routine CMR for positive cases

The University of Wisconsin group looked at all of the institution’s competitive athletes who underwent gadolinium-enhanced CMR imaging and other tests during recovery from COVID-19 from the beginning of the pandemic to the end of November 2020.

The imaging was performed on average about 2 weeks after a first positive SARS-CoV-2 assay result. About one-half and one-fourth of the cohort had experienced mild and moderate symptoms, respectively, and about 17% were asymptomatic; none had been hospitalized.

All CMR scans were reviewed by two experienced radiologists for, among other things, evidence of myocarditis according to modified Lake Louise criteria, the group wrote. Those criteria are based on CMR markers of fibrosis and other characteristics of scarring from myocarditis.

Such evidence was seen in only two members of the cohort, or 1.4%, one with elevated troponins but normal with respect to other biomarkers, and the other negative for all assays. Both were asymptomatic at the time of imaging, the report noted.

The Vanderbilt analysis from Dr. Clark and associates centered on 59 university athletes recently with COVID-19 who underwent CMR imaging along with other tests about 3 weeks after confirmation of SARS-CoV-2 infection. Symptoms had been mild in 78% of the group, and the remainder were asymptomatic.

They were compared with 60 retrospectively identified college athletes and elite-conditioned military personnel who had undergone CMR imaging prior to the advent of COVID-19, and to 27 apparently healthy nonathlete adults in whom CMR had been previously performed to define normal CMR imaging criteria at that center.

The only two post-COVID-19 athletes who met modified Lake Louise criteria for myocarditis showed no abnormalities on ECG or myocardial strain echocardiography, and had normal troponins, the group reported.

The COVID-19 athletes showed increased cardiac chamber volumes and myocardial mass “consistent with athletic remodeling,” compared with the healthy control subjects, the group wrote. But “most standard CMR parameters were similar” between the COVID-19 athletes and the control athletes, consistent with the 22% and 24% rates, respectively, for the finding of focal late LGE isolated to the inferoseptal RV insertion site.

At the end of the day, all published experiences on athletes with recent COVID-19 “are descriptive studies, without any hint of follow-up,” Dr. Baggish noted, so their clinical implications are unknown.

“We need time to sit and watch to see what happens to these individuals,” he said. “And if the answer is nothing, then that’s a very reassuring story. If the answer is that we start to see events, then that’s really important for us to take stock of.”

Dr. Starekova had no disclosures. Dr. Reeder reports that the University of Wisconsin receives research support from GE Healthcare and Bracco Diagnostics; and that he has ownership interests in Calimetrix, Reveal Pharmaceuticals, Cellectar Biosciences, Elucent Medical, and HeartVista; and has received grant support from Bayer Healthcare. Disclosures for the other coauthors are in the report. Dr. Clark and coauthors had no disclosures. Dr. Baggish reported no conflicts. Kim discloses receiving funding from the National Heart, Lung, and Blood Institute; compensation as team cardiologist for the Atlanta Falcons; and research stipends from the Atlanta Track Club.

A version of this article first appeared on Medscape.com.

Two recent observational studies suggest that myocarditis, at least on cardiac magnetic resonance (CMR) imaging, might be far less common in elite-level athletes recovering from COVID-19 than suggested in influential earlier reports.

AlexLMX/Getty Images

Both new studies documented a rate less than one-quarter as high as those previously reported from smaller cohorts, raising questions about the diagnostic yield of CMR in highly conditioned athletes with recent COVID-19 absent other evidence, such as from biomarker assays or electrocardiography (ECG).

That could have implications for some top-tier university athletics programs that mandate CMR imaging, biomarker assays, and other evaluations for myocarditis on all their players who test positive for SARS-CoV-2 before they can return to play.

The findings collectively point to CMR imaging features that might be a hallmark of an athlete’s heart, characterized by normal myocardial remodeling brought on by elite-level exercise training, which in athletes with recent COVID-19 could be misinterpreted as evidence of myocarditis. That may have thrown off prevalence estimates in the literature, the studies’ investigators speculated.

The two studies were retrospective takes on university athletes who underwent CMR imaging while recovering from COVID-19, who were either asymptomatic or with only mild to moderate symptoms and were generally without ECG or troponin evidence of myocarditis.

One of them showed a less than 2% incidence of myocarditis by CMR among 145 such cases, a low yield for imaging that is “raising doubt regarding its utility to evaluate athletes without a clinical presentation or abnormal ancillary tests to support the diagnosis of myocarditis,” argues a report published Jan. 14 in JAMA Cardiology, with lead author Jitka Starekova, MD, University of Wisconsin – Madison.

“Part of the problem is that occult myocarditis is, at least with other viruses, a risk factor for sudden death in competitive athletes. So you don’t want to let one slip through the cracks,” senior author Scott B. Reeder, MD, PhD, from the same institution, said in an interview.

Whether a policy of routine CMR imaging in elite athletes who test positive for the new coronavirus is better than more selective use driven by symptoms or other screening tests is unknown. But the more pressing issue, Dr. Reeder said, “is if they have a normal electrocardiogram and troponins, do they still need cardiac magnetic resonance imaging?”

The current study, he said, “certainly provides helpful evidence that maybe we don’t need as many.”

The other study, which featured two control groups, saw a similarly low incidence of myocarditis by CMR in athletes with recent COVID-19. One of the control groups included university athletes imaged prior to the advent of SARS-CoV-2 in the university’s region of the country. The other consisted of apparently healthy adult nonathletes.

Armed with two non-COVID-19 cohorts and two athlete cohorts, the researchers found comparable rates of myocarditis by CMR in both the COVID-19 athletes and the healthy athletes. And only 3% of the COVID-19 athletes had the tell-tale CMR signs, notes the report, published Dec. 17 in Circulation, with lead author Daniel E. Clark, MD, MPH, Vanderbilt University Medical Center, Nashville, Tenn.
 

Reassurance and concern

“The incidence is much lower than we feared, and so that’s reassuring,” Clark said in an interview. Still, the athletes with myocarditis by CMR “would have been completely missed by a protocol that did not include cardiac MR, and that’s concerning,” he said. “Both had active myocarditis.”

The study’s two non-COVID-19 control groups – elite athletes in one and nonathletes in the other – allowed them to tease out the potential contribution of athletic myocardial remodeling to CMR features that could be interpreted as scar tissue, which are characterized by late gadolinium enhancement (LGE).

As it turned out, focal regions of LGE located in the right ventricular (RV) septum on the scans were often seen in both athlete cohorts. “This kind of trivial nonischemic fibrosis in the mid RV septal insertion site was common among athletic control subjects. It was seen in 24% of them, which is almost identical to the percentage that we saw in the COVID-19 athletes, 22%,” Dr. Clark said.

The LGE finding, wrote Dr. Clark and coauthors, “may represent remodeling from athletic training, and should not be conflated with myocarditis.”

Of note, the other study saw a comparable incidence of the same or a very similar CMR feature in its athletes; 26% of the Wisconsin COVID-19 athlete cohort showed limited focal LGE in the inferior RV insertion site.

“And you get a little bit in the mid-septum, as well,” Dr. Reeder said. But the sign, in the absence of any corresponding T2 abnormalities, was not judged to represent myocarditis. “We interpreted all of these studies with this potential confounder in mind.”

Conceivably, Dr. Reeder proposed, the earlier studies may have “over-called” the prevalence of myocarditis in their cohorts. “I haven’t seen their images, but it’s possible there could be false-positives.”

It’s noteworthy that the Vanderbilt and Wisconsin reports saw closely similar incidences of the tell-tale CMR sign in all the athlete cohorts whether or not COVID-19 was involved, Aaron L. Baggish, MD, Massachusetts General Hospital, Boston, said in an interview.

“It looks very much like just an unrecognized part of athletic remodeling and isn’t in any way, shape, or form implicated as being a COVID-related issue,” said Dr. Baggish, who directs the cardiovascular performance program at his center and is unaffiliated with either study.

Still, that connection remains unproven given how little is yet known about the prevalence of clinically important myocarditis in milder cases of COVID-19, according to an accompanying editorial from Jonathan H. Kim, MD, MSc.

Although isolated LGE at the interventricular RV insertion site is “more commonly described among masters-level endurance athletes, the clinical significance and prevalence of this finding in youthful athletes is uncertain and should not be assumed to be a normal consequence of intense athletic training in young competitive athletes,” argued Dr. Kim, of Emory University, Atlanta.

There’s probably little about being a young competitive athlete that would render a person any more or less prone to COVID-19 cardiac involvement, Dr. Baggish said. Rather, “I think what we’re seeing, as the studies continue to come out, is that prevalence estimates are getting into the low single digits.”

The estimates are similar to those associated with influenza before the COVID-19 age; about 2% of patients showed cardiac involvement, Dr. Baggish said. “So the degree to which COVID is a special virus from this perspective, I think, is still a topic of some debate.”

The two current studies have limitations and neither is positioned to change practice, he said. “I would say that they are both kind of important, reassuring pieces of an unfinished jigsaw puzzle. But we still don’t know what the picture on the puzzle is.”
 

Routine CMR for positive cases

The University of Wisconsin group looked at all of the institution’s competitive athletes who underwent gadolinium-enhanced CMR imaging and other tests during recovery from COVID-19 from the beginning of the pandemic to the end of November 2020.

The imaging was performed on average about 2 weeks after a first positive SARS-CoV-2 assay result. About one-half and one-fourth of the cohort had experienced mild and moderate symptoms, respectively, and about 17% were asymptomatic; none had been hospitalized.

All CMR scans were reviewed by two experienced radiologists for, among other things, evidence of myocarditis according to modified Lake Louise criteria, the group wrote. Those criteria are based on CMR markers of fibrosis and other characteristics of scarring from myocarditis.

Such evidence was seen in only two members of the cohort, or 1.4%, one with elevated troponins but normal with respect to other biomarkers, and the other negative for all assays. Both were asymptomatic at the time of imaging, the report noted.

The Vanderbilt analysis from Dr. Clark and associates centered on 59 university athletes recently with COVID-19 who underwent CMR imaging along with other tests about 3 weeks after confirmation of SARS-CoV-2 infection. Symptoms had been mild in 78% of the group, and the remainder were asymptomatic.

They were compared with 60 retrospectively identified college athletes and elite-conditioned military personnel who had undergone CMR imaging prior to the advent of COVID-19, and to 27 apparently healthy nonathlete adults in whom CMR had been previously performed to define normal CMR imaging criteria at that center.

The only two post-COVID-19 athletes who met modified Lake Louise criteria for myocarditis showed no abnormalities on ECG or myocardial strain echocardiography, and had normal troponins, the group reported.

The COVID-19 athletes showed increased cardiac chamber volumes and myocardial mass “consistent with athletic remodeling,” compared with the healthy control subjects, the group wrote. But “most standard CMR parameters were similar” between the COVID-19 athletes and the control athletes, consistent with the 22% and 24% rates, respectively, for the finding of focal late LGE isolated to the inferoseptal RV insertion site.

At the end of the day, all published experiences on athletes with recent COVID-19 “are descriptive studies, without any hint of follow-up,” Dr. Baggish noted, so their clinical implications are unknown.

“We need time to sit and watch to see what happens to these individuals,” he said. “And if the answer is nothing, then that’s a very reassuring story. If the answer is that we start to see events, then that’s really important for us to take stock of.”

Dr. Starekova had no disclosures. Dr. Reeder reports that the University of Wisconsin receives research support from GE Healthcare and Bracco Diagnostics; and that he has ownership interests in Calimetrix, Reveal Pharmaceuticals, Cellectar Biosciences, Elucent Medical, and HeartVista; and has received grant support from Bayer Healthcare. Disclosures for the other coauthors are in the report. Dr. Clark and coauthors had no disclosures. Dr. Baggish reported no conflicts. Kim discloses receiving funding from the National Heart, Lung, and Blood Institute; compensation as team cardiologist for the Atlanta Falcons; and research stipends from the Atlanta Track Club.

A version of this article first appeared on Medscape.com.

A scoring system that predicts risk for new heart failure over 5 years that is based solely on a few familiar, readily available biomarkers could potentially help steer patients with diabetes or even prediabetes toward HF-preventive therapies, researchers proposed based on a new study.

They foresee the risk-stratification tool, based on data pooled from three major community-based cohort studies but not independently validated, as a way to select patients with diabetes and prediabetes for treatment with SGLT2 inhibitors.

Several members of that drug class, conceived as antidiabetic agents, have been shown to help in prevention or treatment of HF in patients with diabetes and those without diabetes but at increased cardiovascular (CV) risk. Yet their uptake in practice has been lagging, the group noted.

Most HF benefits in the SGLT2 inhibitor trials “were seen in patients who have established cardiovascular disease – basically a history of heart attack or stroke,” Ambarish Pandey, MD, MSCS, University of Texas Southwestern Medical Center, Dallas, said in an interview.

“So we wanted to see how we can identify high-risk patients without a history of cardiovascular disease using these biomarkers, as an approach to targeting SGLT2 inhibitors, which are fairly expensive therapies,” he said. Without such risk stratification, “you end up treating so many more patients to get very modest returns.”

The group developed a scoring system based on four biomarkers that are “easily measured with inexpensive tests,” Dr. Pandey said: high-sensitivity-assay cardiac troponin T (hs-cTnT) and C-reactive protein (hs-CRP) levels, N-terminal of the prohormone brain natriuretic peptide (NT-proBNP) levels, and electrocardiography for evidence of left-ventricular hypertrophy (ECG-LVH).

The derivation cohort consisted of participants in the Atherosclerosis Risk in Communities RIC, Dallas Heart Study, and Multi-Ethnic Study of Atherosclerosis Multi-Ethnic Study of Atherosclerosis epidemiologic studies who were free of coronary heart disease, stroke, or HF for whom there were sufficient data on CV risk factors and the four biomarkers. None were taking SGLT2 inhibitors at enrollment in their respective studies, the researchers noted.

Members of the pooled cohorts who had diabetes or prediabetes were assigned 1 point for each abnormal biomarker. The 5-year risk for incident HF went up continuously along with the score in people with diabetes and in those with prediabetes, the latter defined as a fasting plasma glucose level from 100 mg/dL to less than 126 mg/dL.

For those with a score of 1, compared with 0, for example, the risk for HF went up 82% with diabetes and 40% with prediabetes. But for those with a score of 3 or 4, the risk went up more than four and a half times with diabetes and more than three and a half times for those with prediabetes. Risk increases were independent of other likely HF risk factors and consistently significant.

The analysis was published Jan. 6 in JACC: Heart Failure.

The biomarker score should be especially useful in patients considered at low to intermediate risk, based on clinical characteristics, as a means to identify residual HF risk and, potentially, select candidates for SGLT2-inhibitor therapy, Dr. Pandey said.

“The other purpose of the study was to broaden the scope of heart failure prevention in dysglycemia by looking also at prediabetes, not just diabetes,” he said. There isn’t much high-quality evidence supporting SGLT2-inhibitor therapy in prediabetes, but it follows that the drugs may be helpful in prediabetes because they are protective in patients with and without diabetes.

“Our work suggests that prediabetes patients who have elevated biomarkers are at a higher risk of heart failure,” Dr. Pandey said, suggesting that the HF risk score could potentially help select their drug therapy as well.

The current study seems “to provide a proof of concept that one can use circulating biomarkers to more precisely identify patients in whom therapies might be expected to exert greatest benefit,” which is especially important for potentially expensive agents like the SGLT2 inhibitors, James L. Januzzi, MD, Massachusetts General Hospital, Boston, said in an interview.

Importantly in the analysis, a greater number of biomarker abnormalities not only corresponded to rising levels of risk, the risk increases were “dramatic,” and therefore so was the supposed potential benefit of SGLT2-inhibitor therapy, said Dr. Januzzi, who isn’t a coauthor but was an editor for its publication in JACC: Heart Failure.

The uptake of SGLT2 inhibitors for heart failure in practice has been less rapid than hoped, he observed, so if “this hypothetical construct holds up” for the drug class, “it might actually help kick-start focusing on who might optimally receive the drugs.”

Elevated levels of hs-cTnT, hs-CRP, and NT-proBNP, as well as presence of ECG-LVH, were each independently associated with a significantly increased 5-year risk for HF in unadjusted and adjusted analyses of the 6,799 people in the pooled cohort, 33.2% of whom had diabetes and 66.8% of whom had prediabetes, the group writes.

The scoring system would require validation in other cohorts before it could be used, Dr. Pandey observed; once there is “robust validation,” it might be applied first to patients with dysglycemia at intermediate CV risk by standard clinical measures.

Certainly the HF risk-stratification scoring system requires validation in other studies, Dr. Januzzi agreed. But it is intuitively appealing, and the study’s results are consistent with “data that we’re submitting for publication imminently” based on the CANVAS CV-outcomes trial of the SGLT2 inhibitor canagliflozin (Invokana) in patients with diabetes.

Dr. Pandey disclosed receiving support from the Gilead Sciences Research Scholar Program and serving on an advisory board of Roche Diagnostics. Dr. Januzzi disclosed receiving grant support from Novartis, Applied Therapeutics, and Innolife; consulting for Abbott Diagnostics, Janssen, Novartis, Quidel, and Roche Diagnostics; and serving on end-point committees or data safety monitoring boards for trials supported by Abbott, AbbVie, Amgen, CVRx, Janssen, MyoKardia, and Takeda.

A version of this article first appeared on Medscape.com.

A scoring system that predicts risk for new heart failure over 5 years that is based solely on a few familiar, readily available biomarkers could potentially help steer patients with diabetes or even prediabetes toward HF-preventive therapies, researchers proposed based on a new study.

They foresee the risk-stratification tool, based on data pooled from three major community-based cohort studies but not independently validated, as a way to select patients with diabetes and prediabetes for treatment with SGLT2 inhibitors.

Several members of that drug class, conceived as antidiabetic agents, have been shown to help in prevention or treatment of HF in patients with diabetes and those without diabetes but at increased cardiovascular (CV) risk. Yet their uptake in practice has been lagging, the group noted.

Most HF benefits in the SGLT2 inhibitor trials “were seen in patients who have established cardiovascular disease – basically a history of heart attack or stroke,” Ambarish Pandey, MD, MSCS, University of Texas Southwestern Medical Center, Dallas, said in an interview.

“So we wanted to see how we can identify high-risk patients without a history of cardiovascular disease using these biomarkers, as an approach to targeting SGLT2 inhibitors, which are fairly expensive therapies,” he said. Without such risk stratification, “you end up treating so many more patients to get very modest returns.”

The group developed a scoring system based on four biomarkers that are “easily measured with inexpensive tests,” Dr. Pandey said: high-sensitivity-assay cardiac troponin T (hs-cTnT) and C-reactive protein (hs-CRP) levels, N-terminal of the prohormone brain natriuretic peptide (NT-proBNP) levels, and electrocardiography for evidence of left-ventricular hypertrophy (ECG-LVH).

The derivation cohort consisted of participants in the Atherosclerosis Risk in Communities RIC, Dallas Heart Study, and Multi-Ethnic Study of Atherosclerosis Multi-Ethnic Study of Atherosclerosis epidemiologic studies who were free of coronary heart disease, stroke, or HF for whom there were sufficient data on CV risk factors and the four biomarkers. None were taking SGLT2 inhibitors at enrollment in their respective studies, the researchers noted.

Members of the pooled cohorts who had diabetes or prediabetes were assigned 1 point for each abnormal biomarker. The 5-year risk for incident HF went up continuously along with the score in people with diabetes and in those with prediabetes, the latter defined as a fasting plasma glucose level from 100 mg/dL to less than 126 mg/dL.

For those with a score of 1, compared with 0, for example, the risk for HF went up 82% with diabetes and 40% with prediabetes. But for those with a score of 3 or 4, the risk went up more than four and a half times with diabetes and more than three and a half times for those with prediabetes. Risk increases were independent of other likely HF risk factors and consistently significant.

The analysis was published Jan. 6 in JACC: Heart Failure.

The biomarker score should be especially useful in patients considered at low to intermediate risk, based on clinical characteristics, as a means to identify residual HF risk and, potentially, select candidates for SGLT2-inhibitor therapy, Dr. Pandey said.

“The other purpose of the study was to broaden the scope of heart failure prevention in dysglycemia by looking also at prediabetes, not just diabetes,” he said. There isn’t much high-quality evidence supporting SGLT2-inhibitor therapy in prediabetes, but it follows that the drugs may be helpful in prediabetes because they are protective in patients with and without diabetes.

“Our work suggests that prediabetes patients who have elevated biomarkers are at a higher risk of heart failure,” Dr. Pandey said, suggesting that the HF risk score could potentially help select their drug therapy as well.

The current study seems “to provide a proof of concept that one can use circulating biomarkers to more precisely identify patients in whom therapies might be expected to exert greatest benefit,” which is especially important for potentially expensive agents like the SGLT2 inhibitors, James L. Januzzi, MD, Massachusetts General Hospital, Boston, said in an interview.

Importantly in the analysis, a greater number of biomarker abnormalities not only corresponded to rising levels of risk, the risk increases were “dramatic,” and therefore so was the supposed potential benefit of SGLT2-inhibitor therapy, said Dr. Januzzi, who isn’t a coauthor but was an editor for its publication in JACC: Heart Failure.

The uptake of SGLT2 inhibitors for heart failure in practice has been less rapid than hoped, he observed, so if “this hypothetical construct holds up” for the drug class, “it might actually help kick-start focusing on who might optimally receive the drugs.”

Elevated levels of hs-cTnT, hs-CRP, and NT-proBNP, as well as presence of ECG-LVH, were each independently associated with a significantly increased 5-year risk for HF in unadjusted and adjusted analyses of the 6,799 people in the pooled cohort, 33.2% of whom had diabetes and 66.8% of whom had prediabetes, the group writes.

The scoring system would require validation in other cohorts before it could be used, Dr. Pandey observed; once there is “robust validation,” it might be applied first to patients with dysglycemia at intermediate CV risk by standard clinical measures.

Certainly the HF risk-stratification scoring system requires validation in other studies, Dr. Januzzi agreed. But it is intuitively appealing, and the study’s results are consistent with “data that we’re submitting for publication imminently” based on the CANVAS CV-outcomes trial of the SGLT2 inhibitor canagliflozin (Invokana) in patients with diabetes.

Dr. Pandey disclosed receiving support from the Gilead Sciences Research Scholar Program and serving on an advisory board of Roche Diagnostics. Dr. Januzzi disclosed receiving grant support from Novartis, Applied Therapeutics, and Innolife; consulting for Abbott Diagnostics, Janssen, Novartis, Quidel, and Roche Diagnostics; and serving on end-point committees or data safety monitoring boards for trials supported by Abbott, AbbVie, Amgen, CVRx, Janssen, MyoKardia, and Takeda.

A version of this article first appeared on Medscape.com.

A scoring system that predicts risk for new heart failure over 5 years that is based solely on a few familiar, readily available biomarkers could potentially help steer patients with diabetes or even prediabetes toward HF-preventive therapies, researchers proposed based on a new study.

They foresee the risk-stratification tool, based on data pooled from three major community-based cohort studies but not independently validated, as a way to select patients with diabetes and prediabetes for treatment with SGLT2 inhibitors.

Several members of that drug class, conceived as antidiabetic agents, have been shown to help in prevention or treatment of HF in patients with diabetes and those without diabetes but at increased cardiovascular (CV) risk. Yet their uptake in practice has been lagging, the group noted.

Most HF benefits in the SGLT2 inhibitor trials “were seen in patients who have established cardiovascular disease – basically a history of heart attack or stroke,” Ambarish Pandey, MD, MSCS, University of Texas Southwestern Medical Center, Dallas, said in an interview.

“So we wanted to see how we can identify high-risk patients without a history of cardiovascular disease using these biomarkers, as an approach to targeting SGLT2 inhibitors, which are fairly expensive therapies,” he said. Without such risk stratification, “you end up treating so many more patients to get very modest returns.”

The group developed a scoring system based on four biomarkers that are “easily measured with inexpensive tests,” Dr. Pandey said: high-sensitivity-assay cardiac troponin T (hs-cTnT) and C-reactive protein (hs-CRP) levels, N-terminal of the prohormone brain natriuretic peptide (NT-proBNP) levels, and electrocardiography for evidence of left-ventricular hypertrophy (ECG-LVH).

The derivation cohort consisted of participants in the Atherosclerosis Risk in Communities RIC, Dallas Heart Study, and Multi-Ethnic Study of Atherosclerosis Multi-Ethnic Study of Atherosclerosis epidemiologic studies who were free of coronary heart disease, stroke, or HF for whom there were sufficient data on CV risk factors and the four biomarkers. None were taking SGLT2 inhibitors at enrollment in their respective studies, the researchers noted.

Members of the pooled cohorts who had diabetes or prediabetes were assigned 1 point for each abnormal biomarker. The 5-year risk for incident HF went up continuously along with the score in people with diabetes and in those with prediabetes, the latter defined as a fasting plasma glucose level from 100 mg/dL to less than 126 mg/dL.

For those with a score of 1, compared with 0, for example, the risk for HF went up 82% with diabetes and 40% with prediabetes. But for those with a score of 3 or 4, the risk went up more than four and a half times with diabetes and more than three and a half times for those with prediabetes. Risk increases were independent of other likely HF risk factors and consistently significant.

The analysis was published Jan. 6 in JACC: Heart Failure.

The biomarker score should be especially useful in patients considered at low to intermediate risk, based on clinical characteristics, as a means to identify residual HF risk and, potentially, select candidates for SGLT2-inhibitor therapy, Dr. Pandey said.

“The other purpose of the study was to broaden the scope of heart failure prevention in dysglycemia by looking also at prediabetes, not just diabetes,” he said. There isn’t much high-quality evidence supporting SGLT2-inhibitor therapy in prediabetes, but it follows that the drugs may be helpful in prediabetes because they are protective in patients with and without diabetes.

“Our work suggests that prediabetes patients who have elevated biomarkers are at a higher risk of heart failure,” Dr. Pandey said, suggesting that the HF risk score could potentially help select their drug therapy as well.

The current study seems “to provide a proof of concept that one can use circulating biomarkers to more precisely identify patients in whom therapies might be expected to exert greatest benefit,” which is especially important for potentially expensive agents like the SGLT2 inhibitors, James L. Januzzi, MD, Massachusetts General Hospital, Boston, said in an interview.

Importantly in the analysis, a greater number of biomarker abnormalities not only corresponded to rising levels of risk, the risk increases were “dramatic,” and therefore so was the supposed potential benefit of SGLT2-inhibitor therapy, said Dr. Januzzi, who isn’t a coauthor but was an editor for its publication in JACC: Heart Failure.

The uptake of SGLT2 inhibitors for heart failure in practice has been less rapid than hoped, he observed, so if “this hypothetical construct holds up” for the drug class, “it might actually help kick-start focusing on who might optimally receive the drugs.”

Elevated levels of hs-cTnT, hs-CRP, and NT-proBNP, as well as presence of ECG-LVH, were each independently associated with a significantly increased 5-year risk for HF in unadjusted and adjusted analyses of the 6,799 people in the pooled cohort, 33.2% of whom had diabetes and 66.8% of whom had prediabetes, the group writes.

The scoring system would require validation in other cohorts before it could be used, Dr. Pandey observed; once there is “robust validation,” it might be applied first to patients with dysglycemia at intermediate CV risk by standard clinical measures.

Certainly the HF risk-stratification scoring system requires validation in other studies, Dr. Januzzi agreed. But it is intuitively appealing, and the study’s results are consistent with “data that we’re submitting for publication imminently” based on the CANVAS CV-outcomes trial of the SGLT2 inhibitor canagliflozin (Invokana) in patients with diabetes.

Dr. Pandey disclosed receiving support from the Gilead Sciences Research Scholar Program and serving on an advisory board of Roche Diagnostics. Dr. Januzzi disclosed receiving grant support from Novartis, Applied Therapeutics, and Innolife; consulting for Abbott Diagnostics, Janssen, Novartis, Quidel, and Roche Diagnostics; and serving on end-point committees or data safety monitoring boards for trials supported by Abbott, AbbVie, Amgen, CVRx, Janssen, MyoKardia, and Takeda.

A version of this article first appeared on Medscape.com.

Coronary artery calcium (CAC) score as a measure of plaque burden more reliably predicts future cardiovascular (CV) risk in patients with suspected coronary disease (CAD) than whether or not the disease is obstructive, a large retrospective study suggests.

Indeed, CV risk went up in tandem with growing plaque burden regardless of whether there was obstructive disease in any coronary artery, defined as a 50% or greater stenosis by computed tomographic angiography (CTA).

The findings argue for plaque burden as measured by CAC score, rather than percent-stenosis severity, for guiding further treatment decisions in such patients, researchers say.

The research was based on more than 20,000 symptomatic patients referred to diagnostic CTA in the Western Denmark Heart Registry who were then followed for about 4 years for major CV events, including death, myocardial infarction, or stroke.

“What we show is that CAC is important for prognosis, and that patients with no stenosis have similar high risk as patients with stenosis when CAC burden is similar,” Martin Bødtker Mortensen, MD, PhD, Aarhus (Denmark) University Hospital, said in an interview.

The guidelines “distinguish between primary and secondary prevention patients” based on the presence or absence of obstructive CAD, he said, but “our results challenge this long-held approach. We show that patients with nonobstructive CAD carry similar risk as patients with obstructive CAD.”

In practice, risk tends to be greater in patients with obstructive compared with nonobstructive CAD. But the reason “is simply that they normally have higher atherosclerosis burden,” Dr. Mortensen said. “When you stratify based on atherosclerosis burden, then patients with obstructive and nonobstructive CAD have similar risk.”

The analysis was published online Dec. 7 in the Journal of the American College of Cardiology with Mortensen as lead author.

Until recently, it had long been believed that CV-event risk was driven by ischemia – but “ischemia is just a surrogate for the extent of atherosclerotic disease,” Armin Arbab Zadeh, MD, PhD, MPH, who is not connected with the current study, said in an interview.

The finding that CV risk climbs with growing coronary plaque burden “essentially confirms” other recent studies, but with “added value in showing how well the calcium scores, compared to obstructive disease, track with risk. So it’s definitely a nice extension of the evidence,” said Dr. Zadeh, director of cardiac CT at Johns Hopkins University, Baltimore.

“This study clearly shows that there is no ischemia ‘threshold,’ that the risk starts from mild and goes up with the burden of atherosclerotic disease. We were essentially taught wrong for decades.”

Dr. Mortensen said that the new results “are in line with previous studies showing that atherosclerosis burden is very important for risk.” They also help explain why revascularization of patients with stable angina failed to cut the risk of MI or death in trials like COURAGE, FAME-2, and ISCHEMIA. It’s because “stenosis per se explains little of the risk compared to atherosclerosis burden.”

In the current analysis, for example, about 65% of events were in patients who did not show obstructive CAD at CTA. Its 23,759 patients with symptoms suggestive of CAD were referred for CTA from 2008 through 2017; 5,043 (21.2%) were found to have obstructive disease and 18,716 (78.8%) either had no CAD or nonobstructive disease.

About 4.4% of patients experienced a first major CV event over a median follow-up of 4.3 years. Only events occurring later than 90 days after CTA were counted in an effort to exclude any directly related to revascularization, Dr. Mortensen noted.

The risk of events went up proportionally with both CAC score and the number of coronaries with obstructive disease.

The number of major CV events per 1,000 person-years was 6.2 for patients with a CAC score of 0, of whom 87% had no CAD by CTA, 7% had nonobstructive CAD, and 6% had obstructive CAD.

The corresponding rate was 17.5 among patients with a CAC score >100-399 for a hazard ratio (HR) of 1.7 (95% confidence interval [CI] 1.4-2.1) vs. a CAC score of 0.

And it was 42.3 per 1,000 patient-years among patients with CAC score >1000, HR 3.4 (95% CI, 2.5-4.6) vs. a CAC score of 0. Among those with the highest-tier CAC score, none were without CAD by CTA, 17% had nonobstructive disease, and 83% had obstructive CAD.

The major CV event rate rose similarly by number of coronaries with obstructive disease. It was 6.1 per 1,000 person-years in patients with no CAD. But it was 12.3 in those with nonobstructive disease, HR 1.3 (95% CI 1.1-1.6), up to 34.7 in those with triple-vessel obstructive disease, HR 2.9 (95% CI 2.2-3.9), vs. no CAD.

However, in an analysis with stratification by CAC score tier (0, 1-99, 100-399, 400-1,000, and >1,000), obstructive CAD was not associated with increased major CV-event risk in any stratum. The findings were similar in each subgroup with 1-vessel, 2-vessel, or 3-vessel CAD when stratified by CAC score.

Nor did major CV event risk track with obstructive CAD in analyses by age or after excluding all patients who underwent coronary revascularization within 90 days of CTA, the group reported.

“I believe these results support the use of CTA as a first-line test in patients with symptoms suggestive of CAD, as it provides valuable information for both diagnosis and prognosis in symptomatic patients,” Dr. Mortensen said. Those found to have a higher burden of atherosclerosis, he added, should receive aggressive preventive therapy regardless of whether or not they have obstructive disease.

The evidence from this study and others “supports a CTA-based approach” in such patients, Dr. Zadeh said. “And I would go further to say that a stress test is really inadequate,” in that it “detects the disease at such a late stage, you’re missing the opportunity to identify these patients who have atherosclerotic disease while you can do something about it.”

Its continued use as a first-line test, Dr. Zadeh said, “is essentially, in my mind, dismissing the evidence.”

An accompanying editorial Todd C. Villines, MD, and Patricia Rodriguez Lozano, MD, of the University of Virginia, Charlottesville agreed that “it is time that the traditional definitions of primary and secondary prevention evolve to incorporate CAC and CTA measures of patient risk based on coronary artery plaque burden.”

But they pointed out some limitations of the current study.

“The authors compared CAC with ≥50% stenosis, not CAC to comprehensive, contemporary coronary CTA,” and so “did not assess numerous other well-validated measures of coronary plaque burden that are routinely obtained from coronary CTA that typically improve the prognostic accuracy of coronary CTA beyond stenosis alone.” Also not performed was “plaque quantification on coronary CTA, an emerging field of study.”

The editorialists noted that noncontrast CT as used in the study for CAC scoring “is generally not recommended as a standalone test in symptomatic patients. Most studies have shown that coronary CTA, a test that accurately detects stenosis and identifies all types of coronary atherosclerosis (calcified and noncalcified), has significantly higher diagnostic and prognostic accuracy than CAC when performed in symptomatic patients without known coronary artery disease.”

Dr. Mortensen has disclosed no relevant financial relationships. Disclosures for the other authors are in the report. Dr. Villines and Dr. Rodriguez Lozano have disclosed no relevant financial relationships. Dr. Zadeh disclosed receiving grant support from Canon Medical Systems.

A version of this article originally appeared on Medscape.com.

Coronary artery calcium (CAC) score as a measure of plaque burden more reliably predicts future cardiovascular (CV) risk in patients with suspected coronary disease (CAD) than whether or not the disease is obstructive, a large retrospective study suggests.

Indeed, CV risk went up in tandem with growing plaque burden regardless of whether there was obstructive disease in any coronary artery, defined as a 50% or greater stenosis by computed tomographic angiography (CTA).

The findings argue for plaque burden as measured by CAC score, rather than percent-stenosis severity, for guiding further treatment decisions in such patients, researchers say.

The research was based on more than 20,000 symptomatic patients referred to diagnostic CTA in the Western Denmark Heart Registry who were then followed for about 4 years for major CV events, including death, myocardial infarction, or stroke.

“What we show is that CAC is important for prognosis, and that patients with no stenosis have similar high risk as patients with stenosis when CAC burden is similar,” Martin Bødtker Mortensen, MD, PhD, Aarhus (Denmark) University Hospital, said in an interview.

The guidelines “distinguish between primary and secondary prevention patients” based on the presence or absence of obstructive CAD, he said, but “our results challenge this long-held approach. We show that patients with nonobstructive CAD carry similar risk as patients with obstructive CAD.”

In practice, risk tends to be greater in patients with obstructive compared with nonobstructive CAD. But the reason “is simply that they normally have higher atherosclerosis burden,” Dr. Mortensen said. “When you stratify based on atherosclerosis burden, then patients with obstructive and nonobstructive CAD have similar risk.”

The analysis was published online Dec. 7 in the Journal of the American College of Cardiology with Mortensen as lead author.

Until recently, it had long been believed that CV-event risk was driven by ischemia – but “ischemia is just a surrogate for the extent of atherosclerotic disease,” Armin Arbab Zadeh, MD, PhD, MPH, who is not connected with the current study, said in an interview.

The finding that CV risk climbs with growing coronary plaque burden “essentially confirms” other recent studies, but with “added value in showing how well the calcium scores, compared to obstructive disease, track with risk. So it’s definitely a nice extension of the evidence,” said Dr. Zadeh, director of cardiac CT at Johns Hopkins University, Baltimore.

“This study clearly shows that there is no ischemia ‘threshold,’ that the risk starts from mild and goes up with the burden of atherosclerotic disease. We were essentially taught wrong for decades.”

Dr. Mortensen said that the new results “are in line with previous studies showing that atherosclerosis burden is very important for risk.” They also help explain why revascularization of patients with stable angina failed to cut the risk of MI or death in trials like COURAGE, FAME-2, and ISCHEMIA. It’s because “stenosis per se explains little of the risk compared to atherosclerosis burden.”

In the current analysis, for example, about 65% of events were in patients who did not show obstructive CAD at CTA. Its 23,759 patients with symptoms suggestive of CAD were referred for CTA from 2008 through 2017; 5,043 (21.2%) were found to have obstructive disease and 18,716 (78.8%) either had no CAD or nonobstructive disease.

About 4.4% of patients experienced a first major CV event over a median follow-up of 4.3 years. Only events occurring later than 90 days after CTA were counted in an effort to exclude any directly related to revascularization, Dr. Mortensen noted.

The risk of events went up proportionally with both CAC score and the number of coronaries with obstructive disease.

The number of major CV events per 1,000 person-years was 6.2 for patients with a CAC score of 0, of whom 87% had no CAD by CTA, 7% had nonobstructive CAD, and 6% had obstructive CAD.

The corresponding rate was 17.5 among patients with a CAC score >100-399 for a hazard ratio (HR) of 1.7 (95% confidence interval [CI] 1.4-2.1) vs. a CAC score of 0.

And it was 42.3 per 1,000 patient-years among patients with CAC score >1000, HR 3.4 (95% CI, 2.5-4.6) vs. a CAC score of 0. Among those with the highest-tier CAC score, none were without CAD by CTA, 17% had nonobstructive disease, and 83% had obstructive CAD.

The major CV event rate rose similarly by number of coronaries with obstructive disease. It was 6.1 per 1,000 person-years in patients with no CAD. But it was 12.3 in those with nonobstructive disease, HR 1.3 (95% CI 1.1-1.6), up to 34.7 in those with triple-vessel obstructive disease, HR 2.9 (95% CI 2.2-3.9), vs. no CAD.

However, in an analysis with stratification by CAC score tier (0, 1-99, 100-399, 400-1,000, and >1,000), obstructive CAD was not associated with increased major CV-event risk in any stratum. The findings were similar in each subgroup with 1-vessel, 2-vessel, or 3-vessel CAD when stratified by CAC score.

Nor did major CV event risk track with obstructive CAD in analyses by age or after excluding all patients who underwent coronary revascularization within 90 days of CTA, the group reported.

“I believe these results support the use of CTA as a first-line test in patients with symptoms suggestive of CAD, as it provides valuable information for both diagnosis and prognosis in symptomatic patients,” Dr. Mortensen said. Those found to have a higher burden of atherosclerosis, he added, should receive aggressive preventive therapy regardless of whether or not they have obstructive disease.

The evidence from this study and others “supports a CTA-based approach” in such patients, Dr. Zadeh said. “And I would go further to say that a stress test is really inadequate,” in that it “detects the disease at such a late stage, you’re missing the opportunity to identify these patients who have atherosclerotic disease while you can do something about it.”

Its continued use as a first-line test, Dr. Zadeh said, “is essentially, in my mind, dismissing the evidence.”

An accompanying editorial Todd C. Villines, MD, and Patricia Rodriguez Lozano, MD, of the University of Virginia, Charlottesville agreed that “it is time that the traditional definitions of primary and secondary prevention evolve to incorporate CAC and CTA measures of patient risk based on coronary artery plaque burden.”

But they pointed out some limitations of the current study.

“The authors compared CAC with ≥50% stenosis, not CAC to comprehensive, contemporary coronary CTA,” and so “did not assess numerous other well-validated measures of coronary plaque burden that are routinely obtained from coronary CTA that typically improve the prognostic accuracy of coronary CTA beyond stenosis alone.” Also not performed was “plaque quantification on coronary CTA, an emerging field of study.”

The editorialists noted that noncontrast CT as used in the study for CAC scoring “is generally not recommended as a standalone test in symptomatic patients. Most studies have shown that coronary CTA, a test that accurately detects stenosis and identifies all types of coronary atherosclerosis (calcified and noncalcified), has significantly higher diagnostic and prognostic accuracy than CAC when performed in symptomatic patients without known coronary artery disease.”

Dr. Mortensen has disclosed no relevant financial relationships. Disclosures for the other authors are in the report. Dr. Villines and Dr. Rodriguez Lozano have disclosed no relevant financial relationships. Dr. Zadeh disclosed receiving grant support from Canon Medical Systems.

A version of this article originally appeared on Medscape.com.

Coronary artery calcium (CAC) score as a measure of plaque burden more reliably predicts future cardiovascular (CV) risk in patients with suspected coronary disease (CAD) than whether or not the disease is obstructive, a large retrospective study suggests.

Indeed, CV risk went up in tandem with growing plaque burden regardless of whether there was obstructive disease in any coronary artery, defined as a 50% or greater stenosis by computed tomographic angiography (CTA).

The findings argue for plaque burden as measured by CAC score, rather than percent-stenosis severity, for guiding further treatment decisions in such patients, researchers say.

The research was based on more than 20,000 symptomatic patients referred to diagnostic CTA in the Western Denmark Heart Registry who were then followed for about 4 years for major CV events, including death, myocardial infarction, or stroke.

“What we show is that CAC is important for prognosis, and that patients with no stenosis have similar high risk as patients with stenosis when CAC burden is similar,” Martin Bødtker Mortensen, MD, PhD, Aarhus (Denmark) University Hospital, said in an interview.

The guidelines “distinguish between primary and secondary prevention patients” based on the presence or absence of obstructive CAD, he said, but “our results challenge this long-held approach. We show that patients with nonobstructive CAD carry similar risk as patients with obstructive CAD.”

In practice, risk tends to be greater in patients with obstructive compared with nonobstructive CAD. But the reason “is simply that they normally have higher atherosclerosis burden,” Dr. Mortensen said. “When you stratify based on atherosclerosis burden, then patients with obstructive and nonobstructive CAD have similar risk.”

The analysis was published online Dec. 7 in the Journal of the American College of Cardiology with Mortensen as lead author.

Until recently, it had long been believed that CV-event risk was driven by ischemia – but “ischemia is just a surrogate for the extent of atherosclerotic disease,” Armin Arbab Zadeh, MD, PhD, MPH, who is not connected with the current study, said in an interview.

The finding that CV risk climbs with growing coronary plaque burden “essentially confirms” other recent studies, but with “added value in showing how well the calcium scores, compared to obstructive disease, track with risk. So it’s definitely a nice extension of the evidence,” said Dr. Zadeh, director of cardiac CT at Johns Hopkins University, Baltimore.

“This study clearly shows that there is no ischemia ‘threshold,’ that the risk starts from mild and goes up with the burden of atherosclerotic disease. We were essentially taught wrong for decades.”

Dr. Mortensen said that the new results “are in line with previous studies showing that atherosclerosis burden is very important for risk.” They also help explain why revascularization of patients with stable angina failed to cut the risk of MI or death in trials like COURAGE, FAME-2, and ISCHEMIA. It’s because “stenosis per se explains little of the risk compared to atherosclerosis burden.”

In the current analysis, for example, about 65% of events were in patients who did not show obstructive CAD at CTA. Its 23,759 patients with symptoms suggestive of CAD were referred for CTA from 2008 through 2017; 5,043 (21.2%) were found to have obstructive disease and 18,716 (78.8%) either had no CAD or nonobstructive disease.

About 4.4% of patients experienced a first major CV event over a median follow-up of 4.3 years. Only events occurring later than 90 days after CTA were counted in an effort to exclude any directly related to revascularization, Dr. Mortensen noted.

The risk of events went up proportionally with both CAC score and the number of coronaries with obstructive disease.

The number of major CV events per 1,000 person-years was 6.2 for patients with a CAC score of 0, of whom 87% had no CAD by CTA, 7% had nonobstructive CAD, and 6% had obstructive CAD.

The corresponding rate was 17.5 among patients with a CAC score >100-399 for a hazard ratio (HR) of 1.7 (95% confidence interval [CI] 1.4-2.1) vs. a CAC score of 0.

And it was 42.3 per 1,000 patient-years among patients with CAC score >1000, HR 3.4 (95% CI, 2.5-4.6) vs. a CAC score of 0. Among those with the highest-tier CAC score, none were without CAD by CTA, 17% had nonobstructive disease, and 83% had obstructive CAD.

The major CV event rate rose similarly by number of coronaries with obstructive disease. It was 6.1 per 1,000 person-years in patients with no CAD. But it was 12.3 in those with nonobstructive disease, HR 1.3 (95% CI 1.1-1.6), up to 34.7 in those with triple-vessel obstructive disease, HR 2.9 (95% CI 2.2-3.9), vs. no CAD.

However, in an analysis with stratification by CAC score tier (0, 1-99, 100-399, 400-1,000, and >1,000), obstructive CAD was not associated with increased major CV-event risk in any stratum. The findings were similar in each subgroup with 1-vessel, 2-vessel, or 3-vessel CAD when stratified by CAC score.

Nor did major CV event risk track with obstructive CAD in analyses by age or after excluding all patients who underwent coronary revascularization within 90 days of CTA, the group reported.

“I believe these results support the use of CTA as a first-line test in patients with symptoms suggestive of CAD, as it provides valuable information for both diagnosis and prognosis in symptomatic patients,” Dr. Mortensen said. Those found to have a higher burden of atherosclerosis, he added, should receive aggressive preventive therapy regardless of whether or not they have obstructive disease.

The evidence from this study and others “supports a CTA-based approach” in such patients, Dr. Zadeh said. “And I would go further to say that a stress test is really inadequate,” in that it “detects the disease at such a late stage, you’re missing the opportunity to identify these patients who have atherosclerotic disease while you can do something about it.”

Its continued use as a first-line test, Dr. Zadeh said, “is essentially, in my mind, dismissing the evidence.”

An accompanying editorial Todd C. Villines, MD, and Patricia Rodriguez Lozano, MD, of the University of Virginia, Charlottesville agreed that “it is time that the traditional definitions of primary and secondary prevention evolve to incorporate CAC and CTA measures of patient risk based on coronary artery plaque burden.”

But they pointed out some limitations of the current study.

“The authors compared CAC with ≥50% stenosis, not CAC to comprehensive, contemporary coronary CTA,” and so “did not assess numerous other well-validated measures of coronary plaque burden that are routinely obtained from coronary CTA that typically improve the prognostic accuracy of coronary CTA beyond stenosis alone.” Also not performed was “plaque quantification on coronary CTA, an emerging field of study.”

The editorialists noted that noncontrast CT as used in the study for CAC scoring “is generally not recommended as a standalone test in symptomatic patients. Most studies have shown that coronary CTA, a test that accurately detects stenosis and identifies all types of coronary atherosclerosis (calcified and noncalcified), has significantly higher diagnostic and prognostic accuracy than CAC when performed in symptomatic patients without known coronary artery disease.”

Dr. Mortensen has disclosed no relevant financial relationships. Disclosures for the other authors are in the report. Dr. Villines and Dr. Rodriguez Lozano have disclosed no relevant financial relationships. Dr. Zadeh disclosed receiving grant support from Canon Medical Systems.

A version of this article originally appeared on Medscape.com.

A novel randomized trial taking on a vexing issue around one of the world’s most commonly prescribed medications has concluded that frequently intolerable statin side effects, such as muscle weakness or pain, are almost entirely a nocebo effect, the placebo effect’s darker cousin.

The many patients who report such symptoms while taking statins are indeed probably feeling them, but they are a result of taking the pills rather than any pharmacologic effects, concluded researchers based on their 60-patient study, Self-Assessment Method for Statin Side-effects or Nocebo (SAMSON).

“SAMSON leaves no doubt that patients really do get side effects from statin tablets, but what it shows us is that 90% of this symptomatic burden is elicited by placebo tablets too,” said James P. Howard, MB, PhD, Imperial College London, when presenting the results Nov. 15 at the American Heart Association scientific sessions. They were published simultaneously in the New England Journal of Medicine.

Studies have shown that in practice “more than half of patients abandon statins completely within 2 years. And yet, in placebo-controlled trials, no more people stop statins than placebo,” Dr. Howard said.

“The most important message from SAMSON is that side effects from statin tablets are very real, but they are mainly caused by the act of taking the tablets, not by the statin that is contained within them.”
Patients in the trial, all of whom had a history of dropping statins because of side effects, each took atorvastatin 20 mg/day, a placebo, or neither pill for 1 month, alternating the regimens in randomized order over 1 year so that each was followed a total of 4 months. They used a smartphone app to record the severity of any side effects, not necessarily just pain, on a scale of 0-100.

Symptom intensity scores averaged 16.3 for atorvastatin and 15.4 for placebo, for a nonsignificant difference, but only 8.0 for no-pill months (P < .001 compared with the statin or placebo).
Because such symptoms seem to be based on patient expectations from statin therapy, positive communication about what the drugs can achieve and how the next treatment steps are described can play a big role in their continued use.

For example, “changing them to another statin is a very reasonable thing to do, but as soon as you start trying people on lower doses and working up, you’re sort of telling them that you’re expecting at some dose that they are going to get side effects,” cautioned Dr. Howard at a media briefing on SAMSON.

“The most important thing is to explain the evidence, and what our expectations are, maybe be a bit more optimistic about statins, and tell them they’re very unlikely to suffer from side effects,” he explained, “because the nocebo effect can only really rear its head if the patients are expecting to feel worse – just like the placebo effect will only work if people are expecting to feel better.”
Amit Khera, MD, who moderated the media briefing, said he always tells such patients: “Yes, 1 in 10 patients report having muscle ache. But first and foremost, 9 in 10 don’t. The vast majority of patients don’t get muscle aches. I think that’s really an important part of the communication.”

Now, after SAMSON, “I have an additional point that I’m going to tell them: out of the patients that get muscle aches, probably 90% of that is the anticipation of getting the statin, the nocebo effect,” said Dr. Khera, who directs the preventive cardiology program at the University of Texas Southwestern Medical Center, Dallas.

In practice, however, many patients who report adverse statin effects do so later than 2 weeks after starting therapy, “so these findings cannot be generalized to them,” proposed Francine K. Welty, MD, PhD, Beth Israel Deaconess Medical Center, Boston, as the invited discussant after Dr. Howard’s presentation.

All 60 patients recruited for SAMSON had previously stopped taking a statin because of side effects that arose within 2 weeks of their first dose. That requirement was intended to boost chances that any further symptoms during the trial would arise within a month of starting each new round of pills, Dr. Howard said.

So the trial’s results, Dr. Welty said, “are limited to those subjects who develop symptoms within 2 weeks of starting a statin.”

Including only such patients may have created bias toward a nocebo effect, she said, because “non–drug-related side effects of medications are often greatest during the initial weeks of treatment and tend to abate over time.” For example, “metformin causes diarrhea and beta-blockers cause fatigue, but subjects do adapt and generally tolerate them very well.”

The patients, 25 women and 35 men, 90% of whom were white, received four pill bottles, each with a month’s supply of atorvastatin, four bottles each with 1 month of placebo, and four empty bottles each, to be used double blind for a month in randomized order.

Patients used the smartphone app to document their symptom scores, which ranged from 0 for no symptoms to 100 for symptoms that were the “worst imaginable,” the published report noted. Patients who experienced symptoms so severe as to be intolerable could stop the 1-month regimen they were then following, with instructions to resume the regimens in order starting the next month.

Eleven patients were unable to complete all 12 1-month segments of the trial.

The study’s overall “nocebo ratio” of 0.90 was calculated as the difference between symptom intensity scores on placebo and on no treatment divided by the difference between symptom intensity on the statin and on no treatment. The interpretation: 90% of the symptom burden felt by patients receiving atorvastatin was also felt during placebo use.

A total of 30 patients, contacted 6 months after the trial concluded, had resumed taking a statin, while “4 planned to do so and one could not be contacted,” the report noted. The 25 other patients weren’t receiving a statin and had no plans to take one.

In an important part of the trial, Dr. Howard said, at its conclusion the patients were shown their pattern of symptoms in relation to whether they were taking the statin, placebo, or neither. “Participants could see as clearly as we could the surprisingly powerful magnitude of the nocebo effect. And this led to half of our patients happily restarting statins.”

The implications of SAMSON, Dr. Welty said, “are very important, in that those developing symptoms within 2 weeks of starting a statin should be reassured that approximately half will be able to successful restart the statin.”

SAMSON was funded by the British Heart Foundation. Howard had no disclosures. Dr. Welty disclosed chairing the data safety monitoring committee for Empagliflozin International Clinical Trials, supported by Boehringer Ingelheim.

A version of this article originally appeared on Medscape.com.
 

A novel randomized trial taking on a vexing issue around one of the world’s most commonly prescribed medications has concluded that frequently intolerable statin side effects, such as muscle weakness or pain, are almost entirely a nocebo effect, the placebo effect’s darker cousin.

The many patients who report such symptoms while taking statins are indeed probably feeling them, but they are a result of taking the pills rather than any pharmacologic effects, concluded researchers based on their 60-patient study, Self-Assessment Method for Statin Side-effects or Nocebo (SAMSON).

“SAMSON leaves no doubt that patients really do get side effects from statin tablets, but what it shows us is that 90% of this symptomatic burden is elicited by placebo tablets too,” said James P. Howard, MB, PhD, Imperial College London, when presenting the results Nov. 15 at the American Heart Association scientific sessions. They were published simultaneously in the New England Journal of Medicine.

Studies have shown that in practice “more than half of patients abandon statins completely within 2 years. And yet, in placebo-controlled trials, no more people stop statins than placebo,” Dr. Howard said.

“The most important message from SAMSON is that side effects from statin tablets are very real, but they are mainly caused by the act of taking the tablets, not by the statin that is contained within them.”
Patients in the trial, all of whom had a history of dropping statins because of side effects, each took atorvastatin 20 mg/day, a placebo, or neither pill for 1 month, alternating the regimens in randomized order over 1 year so that each was followed a total of 4 months. They used a smartphone app to record the severity of any side effects, not necessarily just pain, on a scale of 0-100.

Symptom intensity scores averaged 16.3 for atorvastatin and 15.4 for placebo, for a nonsignificant difference, but only 8.0 for no-pill months (P < .001 compared with the statin or placebo).
Because such symptoms seem to be based on patient expectations from statin therapy, positive communication about what the drugs can achieve and how the next treatment steps are described can play a big role in their continued use.

For example, “changing them to another statin is a very reasonable thing to do, but as soon as you start trying people on lower doses and working up, you’re sort of telling them that you’re expecting at some dose that they are going to get side effects,” cautioned Dr. Howard at a media briefing on SAMSON.

“The most important thing is to explain the evidence, and what our expectations are, maybe be a bit more optimistic about statins, and tell them they’re very unlikely to suffer from side effects,” he explained, “because the nocebo effect can only really rear its head if the patients are expecting to feel worse – just like the placebo effect will only work if people are expecting to feel better.”
Amit Khera, MD, who moderated the media briefing, said he always tells such patients: “Yes, 1 in 10 patients report having muscle ache. But first and foremost, 9 in 10 don’t. The vast majority of patients don’t get muscle aches. I think that’s really an important part of the communication.”

Now, after SAMSON, “I have an additional point that I’m going to tell them: out of the patients that get muscle aches, probably 90% of that is the anticipation of getting the statin, the nocebo effect,” said Dr. Khera, who directs the preventive cardiology program at the University of Texas Southwestern Medical Center, Dallas.

In practice, however, many patients who report adverse statin effects do so later than 2 weeks after starting therapy, “so these findings cannot be generalized to them,” proposed Francine K. Welty, MD, PhD, Beth Israel Deaconess Medical Center, Boston, as the invited discussant after Dr. Howard’s presentation.

All 60 patients recruited for SAMSON had previously stopped taking a statin because of side effects that arose within 2 weeks of their first dose. That requirement was intended to boost chances that any further symptoms during the trial would arise within a month of starting each new round of pills, Dr. Howard said.

So the trial’s results, Dr. Welty said, “are limited to those subjects who develop symptoms within 2 weeks of starting a statin.”

Including only such patients may have created bias toward a nocebo effect, she said, because “non–drug-related side effects of medications are often greatest during the initial weeks of treatment and tend to abate over time.” For example, “metformin causes diarrhea and beta-blockers cause fatigue, but subjects do adapt and generally tolerate them very well.”

The patients, 25 women and 35 men, 90% of whom were white, received four pill bottles, each with a month’s supply of atorvastatin, four bottles each with 1 month of placebo, and four empty bottles each, to be used double blind for a month in randomized order.

Patients used the smartphone app to document their symptom scores, which ranged from 0 for no symptoms to 100 for symptoms that were the “worst imaginable,” the published report noted. Patients who experienced symptoms so severe as to be intolerable could stop the 1-month regimen they were then following, with instructions to resume the regimens in order starting the next month.

Eleven patients were unable to complete all 12 1-month segments of the trial.

The study’s overall “nocebo ratio” of 0.90 was calculated as the difference between symptom intensity scores on placebo and on no treatment divided by the difference between symptom intensity on the statin and on no treatment. The interpretation: 90% of the symptom burden felt by patients receiving atorvastatin was also felt during placebo use.

A total of 30 patients, contacted 6 months after the trial concluded, had resumed taking a statin, while “4 planned to do so and one could not be contacted,” the report noted. The 25 other patients weren’t receiving a statin and had no plans to take one.

In an important part of the trial, Dr. Howard said, at its conclusion the patients were shown their pattern of symptoms in relation to whether they were taking the statin, placebo, or neither. “Participants could see as clearly as we could the surprisingly powerful magnitude of the nocebo effect. And this led to half of our patients happily restarting statins.”

The implications of SAMSON, Dr. Welty said, “are very important, in that those developing symptoms within 2 weeks of starting a statin should be reassured that approximately half will be able to successful restart the statin.”

SAMSON was funded by the British Heart Foundation. Howard had no disclosures. Dr. Welty disclosed chairing the data safety monitoring committee for Empagliflozin International Clinical Trials, supported by Boehringer Ingelheim.

A version of this article originally appeared on Medscape.com.
 

A novel randomized trial taking on a vexing issue around one of the world’s most commonly prescribed medications has concluded that frequently intolerable statin side effects, such as muscle weakness or pain, are almost entirely a nocebo effect, the placebo effect’s darker cousin.

The many patients who report such symptoms while taking statins are indeed probably feeling them, but they are a result of taking the pills rather than any pharmacologic effects, concluded researchers based on their 60-patient study, Self-Assessment Method for Statin Side-effects or Nocebo (SAMSON).

“SAMSON leaves no doubt that patients really do get side effects from statin tablets, but what it shows us is that 90% of this symptomatic burden is elicited by placebo tablets too,” said James P. Howard, MB, PhD, Imperial College London, when presenting the results Nov. 15 at the American Heart Association scientific sessions. They were published simultaneously in the New England Journal of Medicine.

Studies have shown that in practice “more than half of patients abandon statins completely within 2 years. And yet, in placebo-controlled trials, no more people stop statins than placebo,” Dr. Howard said.

“The most important message from SAMSON is that side effects from statin tablets are very real, but they are mainly caused by the act of taking the tablets, not by the statin that is contained within them.”
Patients in the trial, all of whom had a history of dropping statins because of side effects, each took atorvastatin 20 mg/day, a placebo, or neither pill for 1 month, alternating the regimens in randomized order over 1 year so that each was followed a total of 4 months. They used a smartphone app to record the severity of any side effects, not necessarily just pain, on a scale of 0-100.

Symptom intensity scores averaged 16.3 for atorvastatin and 15.4 for placebo, for a nonsignificant difference, but only 8.0 for no-pill months (P < .001 compared with the statin or placebo).
Because such symptoms seem to be based on patient expectations from statin therapy, positive communication about what the drugs can achieve and how the next treatment steps are described can play a big role in their continued use.

For example, “changing them to another statin is a very reasonable thing to do, but as soon as you start trying people on lower doses and working up, you’re sort of telling them that you’re expecting at some dose that they are going to get side effects,” cautioned Dr. Howard at a media briefing on SAMSON.

“The most important thing is to explain the evidence, and what our expectations are, maybe be a bit more optimistic about statins, and tell them they’re very unlikely to suffer from side effects,” he explained, “because the nocebo effect can only really rear its head if the patients are expecting to feel worse – just like the placebo effect will only work if people are expecting to feel better.”
Amit Khera, MD, who moderated the media briefing, said he always tells such patients: “Yes, 1 in 10 patients report having muscle ache. But first and foremost, 9 in 10 don’t. The vast majority of patients don’t get muscle aches. I think that’s really an important part of the communication.”

Now, after SAMSON, “I have an additional point that I’m going to tell them: out of the patients that get muscle aches, probably 90% of that is the anticipation of getting the statin, the nocebo effect,” said Dr. Khera, who directs the preventive cardiology program at the University of Texas Southwestern Medical Center, Dallas.

In practice, however, many patients who report adverse statin effects do so later than 2 weeks after starting therapy, “so these findings cannot be generalized to them,” proposed Francine K. Welty, MD, PhD, Beth Israel Deaconess Medical Center, Boston, as the invited discussant after Dr. Howard’s presentation.

All 60 patients recruited for SAMSON had previously stopped taking a statin because of side effects that arose within 2 weeks of their first dose. That requirement was intended to boost chances that any further symptoms during the trial would arise within a month of starting each new round of pills, Dr. Howard said.

So the trial’s results, Dr. Welty said, “are limited to those subjects who develop symptoms within 2 weeks of starting a statin.”

Including only such patients may have created bias toward a nocebo effect, she said, because “non–drug-related side effects of medications are often greatest during the initial weeks of treatment and tend to abate over time.” For example, “metformin causes diarrhea and beta-blockers cause fatigue, but subjects do adapt and generally tolerate them very well.”

The patients, 25 women and 35 men, 90% of whom were white, received four pill bottles, each with a month’s supply of atorvastatin, four bottles each with 1 month of placebo, and four empty bottles each, to be used double blind for a month in randomized order.

Patients used the smartphone app to document their symptom scores, which ranged from 0 for no symptoms to 100 for symptoms that were the “worst imaginable,” the published report noted. Patients who experienced symptoms so severe as to be intolerable could stop the 1-month regimen they were then following, with instructions to resume the regimens in order starting the next month.

Eleven patients were unable to complete all 12 1-month segments of the trial.

The study’s overall “nocebo ratio” of 0.90 was calculated as the difference between symptom intensity scores on placebo and on no treatment divided by the difference between symptom intensity on the statin and on no treatment. The interpretation: 90% of the symptom burden felt by patients receiving atorvastatin was also felt during placebo use.

A total of 30 patients, contacted 6 months after the trial concluded, had resumed taking a statin, while “4 planned to do so and one could not be contacted,” the report noted. The 25 other patients weren’t receiving a statin and had no plans to take one.

In an important part of the trial, Dr. Howard said, at its conclusion the patients were shown their pattern of symptoms in relation to whether they were taking the statin, placebo, or neither. “Participants could see as clearly as we could the surprisingly powerful magnitude of the nocebo effect. And this led to half of our patients happily restarting statins.”

The implications of SAMSON, Dr. Welty said, “are very important, in that those developing symptoms within 2 weeks of starting a statin should be reassured that approximately half will be able to successful restart the statin.”

SAMSON was funded by the British Heart Foundation. Howard had no disclosures. Dr. Welty disclosed chairing the data safety monitoring committee for Empagliflozin International Clinical Trials, supported by Boehringer Ingelheim.

A version of this article originally appeared on Medscape.com.
 

Clinical trials of omega-3 fatty acid or vitamin D supplements have followed a long and winding road in search of benefits in cardiovascular (CV) disease, with wildly mixed results. But the journey may be in vain in one of cardiology’s frontier research areas, primary prevention of atrial fibrillation (AF), suggest primary results of the VITAL-Rhythm trial, presented Nov. 13 during the  American Heart Association (AHA) Scientific Sessions 2020 virtual meeting.

Neither marine-oil caps nor the vitamin D3 supplements made a difference to risk for incident AF, whether paroxysmal or persistent, over more than 5 years in the study, with more than 25,000 adults in the community. Nor did they seem to cause harm.

“To our knowledge, this is the first large-scale, long-term, randomized placebo-controlled trial to test the effect of any intervention on incident AF,” Christine M. Albert, MD, MPH, Cedars-Sinai Medical Center in Los Angeles, said at a media briefing on VITAL-Rhythm before her formal presentation of the trial during the conference.

Its findings, she said, don’t support the use of marine-oil caps or vitamin D3 for primary prevention of incident AF. “Fortunately, they also do not show any increased risk in atrial fibrillation for patients who are using these supplements for other indications.”

Both agents are widely taken without physician supervision for their perceived benefits, and marine-oil caps in particular – often in special prescription formulations – may be used for reducing elevated triglyceride levels and, based on the results of REDUCE-IT, cutting cardiovascular risk.

“It’s pretty clear that there’s no evidence to suggest that either of these supplements is helpful for preventing atrial fibrillation. And I think that’s clear from the evidence these investigators presented,” said Jonathan P. Piccini, MD, MHS, Duke University, Durham, N.C., who wasn’t part of the study.

“It’s also a little disappointing because atrial fibrillation is such a huge problem, and the inability to identify preventative strategies is a repeated theme,” he said in an interview.
VITAL-Rhythm is an ancillary study within the VITAL trial, which showed no benefit from either supplement regarding risk for incident cancer or CV events, as reported at the AHA sessions 2 years ago. In fact, their effects seem sweepingly negative throughout the trial; in another ancillary study, VITAL-DKD, neither supplement helped preserve renal function over 5 years in patients with type 2 diabetes.   

The participants started VITAL without a history of AF, CV disease, or cancer; they were randomly assigned to take about a gram of omega-3 fatty acids, 2000 IU vitamin D3 daily, or their placebos, in a double randomization.

VITAL and its ancillary studies collectively undercut mechanistic theories about how omega-3 fatty acid and vitamin D supplements may affect AF risk, ideas derived from epidemiologic and dietary studies. They were thought perhaps “to have direct antiarrhythmic effects on myocytes through effects on ion channels, electrical remodeling, electrical stabilizing effects, and fluidity of the cell membranes,” observed Renate B. Schnabel, MD, MSc, University Heart Center, Hamburg, Germany, at the briefing. Or such effects might be related to beneficial effects on atherosclerosis, inflammation, or ischemic heart disease, she noted.

Neither idea is likely after VITAL and VITAL-Rhythm, said Dr. Schnabel, who spoke as an invited discussant after Albert’s formal presentation at AHA 2020.

That omega-3 fatty acid supplements may not improve AF incidence or risks has also been evident from many clinical trials and observational studies. Several, including REDUCE-IT, included some evidence for increasing risk for AF with marine-oil supplement intake. That may have happened in VITAL-Rhythm as well.

“While there was no evidence that the omega-3 three fatty acids prevented atrial fibrillation, there was a signal of perhaps more atrial fibrillation in the omega-3 fatty-acids group,” said Dr. Piccini, who directs his center’s electrophysiology clinical trials program.

A sensitivity analysis limited to participants who adhered to their assigned regimens, as opposed to the main intention-to-treat (ITT) analysis, showed a nonsignificant 13% increased hazard ratio for incident AF for the marine-oil supplement group. It reached a P value of .09, which can be interpreted as a trend.

“There are a few studies that have now showed a trend or an increased incidence of arrhythmia in patients treated with omega-3 fatty acids,” Dr. Piccini noted. “I don’t think it’s definitive, but it’s certainly something to keep an eye on.”

VITAL-Rhythm included an electrocardiography (ECG) substudy, yet to be reported, that should yield more insights about any such effects of marine-oil or vitamin D supplements in the trial, Dr. Albert said at the briefing.

The ancillary study assigned its 25,119 patients (mean age, 67 years; 51% women) to take vitamin D3 at 2000 IU/day, marine-oil supplements containing omega-3 fatty acids at 840 mg per day – 460 mg eicosapentaenoic acid (EPA) plus 380 mg docosahexaenoic acid (DHA) (Omacor, Pronova BioPharma) – or their placebos in a 2 x 2 randomization.

Incident cases of AF were identified through annual questionnaires in which the participants self-reported whether they had received a physician diagnosis of the arrhythmia, supplemented by Centers for Medicare & Medicaid Services claims data for AF hospital and clinical visits. Those led to a review of inpatient and outpatient records, from which AF events were adjudicated by an endpoint committee.

An electrocardiogram (72.9%) or physician’s report (27.1%) confirmed the AF diagnosis as the protocol required.

By those standards, 900 incident cases were identified, for a rate of 3.6% over a median of 5.3 years. They were paroxysmal in 58.4%, persistent in 38.4%, and indeterminant in 3.1%, Dr. Albert reported.

Of the 12,542 patients assigned to marine-oil caps by ITT, 469 (3.74%) developed incident AF in the ITT analysis, compared to 431 of 12,577 (3.43%) who received placebo, for an adjusted hazard ratio (HR) of 1.09 (95% CI, 0.96-1.24; P = .19).

The results were similar in two sensitivity analyses, one of which omitted patients with AF who may have had symptoms before randomization and another excluding those whose incident AF was identified solely in CMS data. But in the third “on treatment” sensitivity analysis, the HR for events was 1.13 (95% CI, 0.98-1.30; P = .09).

Outcomes for the vitamin D randomization were nearly the same, for an HR of 1.09 (95% CI, 0.96-1.25; P = .19) by ITT; the results were similar in all three sensitivity analyses.

“It’s not a tremendous signal of risk,” said Piccini of the marine-oil on-treatment analysis. But it, along with consistent evidence from other studies, does give him pause. “If a patient came to me and said,

Doctor, I want to take omega-3 fish oil, because I want to reduce my risk of events, as an arrhythmia doctor I would say, ‘We don’t have great evidence to do that for preventing atrial fibrillation. And there’s actually some evidence that it could mildly increase your risk of developing it.’ ”

For those prescribed evidence-based marine-oil therapy for other indications, he said, “I think the take-home message certainly is, if they report palpitations or other signs or symptoms that could be due to atrial fibrillation, we should be aggressive about screening for atrial fibrillation,” and making the diagnosis as appropriate. If the incident AF resolves after stopping the treatment, “maybe it’s reasonable to refrain from prescribing the medication for that patient.”

VITAL-Rhythm and VITAL are supported by multiple grants from the National Institutes of Health. Albert discloses receiving grant support from St. Jude Medical, Abbott, and Roche. Schnabel reports receiving honoraria from Bristol-Myers Squibb/Pfizer. Piccini previously disclosed receiving research grants from Abbott, the Association for the Advancement of Medical Instrumentation, Bayer, Boston Scientific, and Philips and serving as a consultant to Abbott, Allergan, ARCA Biopharma, Biotronik, Boston Scientific, LivaNova, Medtronic, Milestone, Sanofi, Philips, and UptoDate.

A version of this article originally appeared on Medscape.com.

Clinical trials of omega-3 fatty acid or vitamin D supplements have followed a long and winding road in search of benefits in cardiovascular (CV) disease, with wildly mixed results. But the journey may be in vain in one of cardiology’s frontier research areas, primary prevention of atrial fibrillation (AF), suggest primary results of the VITAL-Rhythm trial, presented Nov. 13 during the  American Heart Association (AHA) Scientific Sessions 2020 virtual meeting.

Neither marine-oil caps nor the vitamin D3 supplements made a difference to risk for incident AF, whether paroxysmal or persistent, over more than 5 years in the study, with more than 25,000 adults in the community. Nor did they seem to cause harm.

“To our knowledge, this is the first large-scale, long-term, randomized placebo-controlled trial to test the effect of any intervention on incident AF,” Christine M. Albert, MD, MPH, Cedars-Sinai Medical Center in Los Angeles, said at a media briefing on VITAL-Rhythm before her formal presentation of the trial during the conference.

Its findings, she said, don’t support the use of marine-oil caps or vitamin D3 for primary prevention of incident AF. “Fortunately, they also do not show any increased risk in atrial fibrillation for patients who are using these supplements for other indications.”

Both agents are widely taken without physician supervision for their perceived benefits, and marine-oil caps in particular – often in special prescription formulations – may be used for reducing elevated triglyceride levels and, based on the results of REDUCE-IT, cutting cardiovascular risk.

“It’s pretty clear that there’s no evidence to suggest that either of these supplements is helpful for preventing atrial fibrillation. And I think that’s clear from the evidence these investigators presented,” said Jonathan P. Piccini, MD, MHS, Duke University, Durham, N.C., who wasn’t part of the study.

“It’s also a little disappointing because atrial fibrillation is such a huge problem, and the inability to identify preventative strategies is a repeated theme,” he said in an interview.
VITAL-Rhythm is an ancillary study within the VITAL trial, which showed no benefit from either supplement regarding risk for incident cancer or CV events, as reported at the AHA sessions 2 years ago. In fact, their effects seem sweepingly negative throughout the trial; in another ancillary study, VITAL-DKD, neither supplement helped preserve renal function over 5 years in patients with type 2 diabetes.   

The participants started VITAL without a history of AF, CV disease, or cancer; they were randomly assigned to take about a gram of omega-3 fatty acids, 2000 IU vitamin D3 daily, or their placebos, in a double randomization.

VITAL and its ancillary studies collectively undercut mechanistic theories about how omega-3 fatty acid and vitamin D supplements may affect AF risk, ideas derived from epidemiologic and dietary studies. They were thought perhaps “to have direct antiarrhythmic effects on myocytes through effects on ion channels, electrical remodeling, electrical stabilizing effects, and fluidity of the cell membranes,” observed Renate B. Schnabel, MD, MSc, University Heart Center, Hamburg, Germany, at the briefing. Or such effects might be related to beneficial effects on atherosclerosis, inflammation, or ischemic heart disease, she noted.

Neither idea is likely after VITAL and VITAL-Rhythm, said Dr. Schnabel, who spoke as an invited discussant after Albert’s formal presentation at AHA 2020.

That omega-3 fatty acid supplements may not improve AF incidence or risks has also been evident from many clinical trials and observational studies. Several, including REDUCE-IT, included some evidence for increasing risk for AF with marine-oil supplement intake. That may have happened in VITAL-Rhythm as well.

“While there was no evidence that the omega-3 three fatty acids prevented atrial fibrillation, there was a signal of perhaps more atrial fibrillation in the omega-3 fatty-acids group,” said Dr. Piccini, who directs his center’s electrophysiology clinical trials program.

A sensitivity analysis limited to participants who adhered to their assigned regimens, as opposed to the main intention-to-treat (ITT) analysis, showed a nonsignificant 13% increased hazard ratio for incident AF for the marine-oil supplement group. It reached a P value of .09, which can be interpreted as a trend.

“There are a few studies that have now showed a trend or an increased incidence of arrhythmia in patients treated with omega-3 fatty acids,” Dr. Piccini noted. “I don’t think it’s definitive, but it’s certainly something to keep an eye on.”

VITAL-Rhythm included an electrocardiography (ECG) substudy, yet to be reported, that should yield more insights about any such effects of marine-oil or vitamin D supplements in the trial, Dr. Albert said at the briefing.

The ancillary study assigned its 25,119 patients (mean age, 67 years; 51% women) to take vitamin D3 at 2000 IU/day, marine-oil supplements containing omega-3 fatty acids at 840 mg per day – 460 mg eicosapentaenoic acid (EPA) plus 380 mg docosahexaenoic acid (DHA) (Omacor, Pronova BioPharma) – or their placebos in a 2 x 2 randomization.

Incident cases of AF were identified through annual questionnaires in which the participants self-reported whether they had received a physician diagnosis of the arrhythmia, supplemented by Centers for Medicare & Medicaid Services claims data for AF hospital and clinical visits. Those led to a review of inpatient and outpatient records, from which AF events were adjudicated by an endpoint committee.

An electrocardiogram (72.9%) or physician’s report (27.1%) confirmed the AF diagnosis as the protocol required.

By those standards, 900 incident cases were identified, for a rate of 3.6% over a median of 5.3 years. They were paroxysmal in 58.4%, persistent in 38.4%, and indeterminant in 3.1%, Dr. Albert reported.

Of the 12,542 patients assigned to marine-oil caps by ITT, 469 (3.74%) developed incident AF in the ITT analysis, compared to 431 of 12,577 (3.43%) who received placebo, for an adjusted hazard ratio (HR) of 1.09 (95% CI, 0.96-1.24; P = .19).

The results were similar in two sensitivity analyses, one of which omitted patients with AF who may have had symptoms before randomization and another excluding those whose incident AF was identified solely in CMS data. But in the third “on treatment” sensitivity analysis, the HR for events was 1.13 (95% CI, 0.98-1.30; P = .09).

Outcomes for the vitamin D randomization were nearly the same, for an HR of 1.09 (95% CI, 0.96-1.25; P = .19) by ITT; the results were similar in all three sensitivity analyses.

“It’s not a tremendous signal of risk,” said Piccini of the marine-oil on-treatment analysis. But it, along with consistent evidence from other studies, does give him pause. “If a patient came to me and said,

Doctor, I want to take omega-3 fish oil, because I want to reduce my risk of events, as an arrhythmia doctor I would say, ‘We don’t have great evidence to do that for preventing atrial fibrillation. And there’s actually some evidence that it could mildly increase your risk of developing it.’ ”

For those prescribed evidence-based marine-oil therapy for other indications, he said, “I think the take-home message certainly is, if they report palpitations or other signs or symptoms that could be due to atrial fibrillation, we should be aggressive about screening for atrial fibrillation,” and making the diagnosis as appropriate. If the incident AF resolves after stopping the treatment, “maybe it’s reasonable to refrain from prescribing the medication for that patient.”

VITAL-Rhythm and VITAL are supported by multiple grants from the National Institutes of Health. Albert discloses receiving grant support from St. Jude Medical, Abbott, and Roche. Schnabel reports receiving honoraria from Bristol-Myers Squibb/Pfizer. Piccini previously disclosed receiving research grants from Abbott, the Association for the Advancement of Medical Instrumentation, Bayer, Boston Scientific, and Philips and serving as a consultant to Abbott, Allergan, ARCA Biopharma, Biotronik, Boston Scientific, LivaNova, Medtronic, Milestone, Sanofi, Philips, and UptoDate.

A version of this article originally appeared on Medscape.com.

Clinical trials of omega-3 fatty acid or vitamin D supplements have followed a long and winding road in search of benefits in cardiovascular (CV) disease, with wildly mixed results. But the journey may be in vain in one of cardiology’s frontier research areas, primary prevention of atrial fibrillation (AF), suggest primary results of the VITAL-Rhythm trial, presented Nov. 13 during the  American Heart Association (AHA) Scientific Sessions 2020 virtual meeting.

Neither marine-oil caps nor the vitamin D3 supplements made a difference to risk for incident AF, whether paroxysmal or persistent, over more than 5 years in the study, with more than 25,000 adults in the community. Nor did they seem to cause harm.

“To our knowledge, this is the first large-scale, long-term, randomized placebo-controlled trial to test the effect of any intervention on incident AF,” Christine M. Albert, MD, MPH, Cedars-Sinai Medical Center in Los Angeles, said at a media briefing on VITAL-Rhythm before her formal presentation of the trial during the conference.

Its findings, she said, don’t support the use of marine-oil caps or vitamin D3 for primary prevention of incident AF. “Fortunately, they also do not show any increased risk in atrial fibrillation for patients who are using these supplements for other indications.”

Both agents are widely taken without physician supervision for their perceived benefits, and marine-oil caps in particular – often in special prescription formulations – may be used for reducing elevated triglyceride levels and, based on the results of REDUCE-IT, cutting cardiovascular risk.

“It’s pretty clear that there’s no evidence to suggest that either of these supplements is helpful for preventing atrial fibrillation. And I think that’s clear from the evidence these investigators presented,” said Jonathan P. Piccini, MD, MHS, Duke University, Durham, N.C., who wasn’t part of the study.

“It’s also a little disappointing because atrial fibrillation is such a huge problem, and the inability to identify preventative strategies is a repeated theme,” he said in an interview.
VITAL-Rhythm is an ancillary study within the VITAL trial, which showed no benefit from either supplement regarding risk for incident cancer or CV events, as reported at the AHA sessions 2 years ago. In fact, their effects seem sweepingly negative throughout the trial; in another ancillary study, VITAL-DKD, neither supplement helped preserve renal function over 5 years in patients with type 2 diabetes.   

The participants started VITAL without a history of AF, CV disease, or cancer; they were randomly assigned to take about a gram of omega-3 fatty acids, 2000 IU vitamin D3 daily, or their placebos, in a double randomization.

VITAL and its ancillary studies collectively undercut mechanistic theories about how omega-3 fatty acid and vitamin D supplements may affect AF risk, ideas derived from epidemiologic and dietary studies. They were thought perhaps “to have direct antiarrhythmic effects on myocytes through effects on ion channels, electrical remodeling, electrical stabilizing effects, and fluidity of the cell membranes,” observed Renate B. Schnabel, MD, MSc, University Heart Center, Hamburg, Germany, at the briefing. Or such effects might be related to beneficial effects on atherosclerosis, inflammation, or ischemic heart disease, she noted.

Neither idea is likely after VITAL and VITAL-Rhythm, said Dr. Schnabel, who spoke as an invited discussant after Albert’s formal presentation at AHA 2020.

That omega-3 fatty acid supplements may not improve AF incidence or risks has also been evident from many clinical trials and observational studies. Several, including REDUCE-IT, included some evidence for increasing risk for AF with marine-oil supplement intake. That may have happened in VITAL-Rhythm as well.

“While there was no evidence that the omega-3 three fatty acids prevented atrial fibrillation, there was a signal of perhaps more atrial fibrillation in the omega-3 fatty-acids group,” said Dr. Piccini, who directs his center’s electrophysiology clinical trials program.

A sensitivity analysis limited to participants who adhered to their assigned regimens, as opposed to the main intention-to-treat (ITT) analysis, showed a nonsignificant 13% increased hazard ratio for incident AF for the marine-oil supplement group. It reached a P value of .09, which can be interpreted as a trend.

“There are a few studies that have now showed a trend or an increased incidence of arrhythmia in patients treated with omega-3 fatty acids,” Dr. Piccini noted. “I don’t think it’s definitive, but it’s certainly something to keep an eye on.”

VITAL-Rhythm included an electrocardiography (ECG) substudy, yet to be reported, that should yield more insights about any such effects of marine-oil or vitamin D supplements in the trial, Dr. Albert said at the briefing.

The ancillary study assigned its 25,119 patients (mean age, 67 years; 51% women) to take vitamin D3 at 2000 IU/day, marine-oil supplements containing omega-3 fatty acids at 840 mg per day – 460 mg eicosapentaenoic acid (EPA) plus 380 mg docosahexaenoic acid (DHA) (Omacor, Pronova BioPharma) – or their placebos in a 2 x 2 randomization.

Incident cases of AF were identified through annual questionnaires in which the participants self-reported whether they had received a physician diagnosis of the arrhythmia, supplemented by Centers for Medicare & Medicaid Services claims data for AF hospital and clinical visits. Those led to a review of inpatient and outpatient records, from which AF events were adjudicated by an endpoint committee.

An electrocardiogram (72.9%) or physician’s report (27.1%) confirmed the AF diagnosis as the protocol required.

By those standards, 900 incident cases were identified, for a rate of 3.6% over a median of 5.3 years. They were paroxysmal in 58.4%, persistent in 38.4%, and indeterminant in 3.1%, Dr. Albert reported.

Of the 12,542 patients assigned to marine-oil caps by ITT, 469 (3.74%) developed incident AF in the ITT analysis, compared to 431 of 12,577 (3.43%) who received placebo, for an adjusted hazard ratio (HR) of 1.09 (95% CI, 0.96-1.24; P = .19).

The results were similar in two sensitivity analyses, one of which omitted patients with AF who may have had symptoms before randomization and another excluding those whose incident AF was identified solely in CMS data. But in the third “on treatment” sensitivity analysis, the HR for events was 1.13 (95% CI, 0.98-1.30; P = .09).

Outcomes for the vitamin D randomization were nearly the same, for an HR of 1.09 (95% CI, 0.96-1.25; P = .19) by ITT; the results were similar in all three sensitivity analyses.

“It’s not a tremendous signal of risk,” said Piccini of the marine-oil on-treatment analysis. But it, along with consistent evidence from other studies, does give him pause. “If a patient came to me and said,

Doctor, I want to take omega-3 fish oil, because I want to reduce my risk of events, as an arrhythmia doctor I would say, ‘We don’t have great evidence to do that for preventing atrial fibrillation. And there’s actually some evidence that it could mildly increase your risk of developing it.’ ”

For those prescribed evidence-based marine-oil therapy for other indications, he said, “I think the take-home message certainly is, if they report palpitations or other signs or symptoms that could be due to atrial fibrillation, we should be aggressive about screening for atrial fibrillation,” and making the diagnosis as appropriate. If the incident AF resolves after stopping the treatment, “maybe it’s reasonable to refrain from prescribing the medication for that patient.”

VITAL-Rhythm and VITAL are supported by multiple grants from the National Institutes of Health. Albert discloses receiving grant support from St. Jude Medical, Abbott, and Roche. Schnabel reports receiving honoraria from Bristol-Myers Squibb/Pfizer. Piccini previously disclosed receiving research grants from Abbott, the Association for the Advancement of Medical Instrumentation, Bayer, Boston Scientific, and Philips and serving as a consultant to Abbott, Allergan, ARCA Biopharma, Biotronik, Boston Scientific, LivaNova, Medtronic, Milestone, Sanofi, Philips, and UptoDate.

A version of this article originally appeared on Medscape.com.

Cardiologists are already old hands at virtual meetings this year and are fast becoming experts on Zoom and other teleconferencing platforms, if not on how to unmute their microphones.

With expectations perhaps elevated and the new communications genre’s novelty on the wane, the American Heart Association (AHA) Scientific Sessions 2020 has a chance to both innovate with familiar formats and captivate with the field’s latest research findings.

Although the virtual AHA 2020 might not satisfy longings for face-to-face networking, shop talk, or kidding around over coffee, it will feature many traditional elements of the live conferences adapted for ear buds and small screens. They include late-breaking science (LBS) presentations and panel discussions, poster and live oral abstract presentations, meet-the-trialist talks, fireside-chat discussion forums, early career events, and satellite symposia.

The event may well hold lessons for future iterations of AHA Scientific Sessions in the postpandemic world, which some foresee as, potentially, an amalgam of the time-honored live format and a robust, complementary online presence.

Late-Breaking Science 1. Friday, November 13, 10:30 AM - 11:30 AM CST

The LBS sessions launch with the GALACTIC-HF trial, which — the world recently learned — may expand the burgeoning list of meds shown to improve clinical outcomes in chronic heart failure (HF) with reduced ejection fraction (HFrEF).

In cursory top-line results announced last month, those in the trial of more than 8000 patients who were randomly assigned to receive omecamtiv mecarbil (Amgen/Cytokinetics/Servier) showed a slight but significant benefit for the primary end point of cardiovascular (CV) death or HF events. The hazard ratio (HR), compared with standard care, was 0.92 (95% CI, 0.86 - 0.99; P = .025), noted a press release from Amgen.

Among the announcement’s few other details was a short take on safety outcomes: no difference in risk for “adverse events, including major ischemic cardiac events,” between the active and control groups. The presentation is sure to provide further insights and caveats, if any, along with other information crucial to the study’s interpretation.

Next on the schedule is the closely watched AFFIRM-AHF, billed as the first major outcomes trial of iron administration to iron-deficient patients with acute HF. It randomly assigned more than 1000 such patients to receive IV ferric carboxymaltose or a placebo. The first dose was given in-hospital and subsequent doses at home for 24 weeks or until patients were no longer iron deficient. They were followed to 1 year for the primary end point of recurrent HF hospitalizations or CV death.

The session wraps with the VITAL Rhythm trial, a substudy of the doubly randomized VITAL trial that explored the effects of vitamin D and omega-3 fatty acid supplementation on CV and cancer risk in more than 25,000 patients in the community. The substudy explored the effects of two active therapies, a preparation of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (Omacor, Reliant Pharmaceuticals) or vitamin D3 supplements, on new-onset atrial fibrillation (AF) as the primary end point; it also looked at risk for sudden death.
 

Late-Breaking Science 2. Friday, November 13, 12:00 PM - 1:00 PM CST

Dominating the session in two presentations, the (TIPS)-3 trial explored a polypill primary-prevention strategy and daily aspirin with vitamin D supplementation in three separate placebo-controlled comparisons in more than 5700 “intermediate risk” participants 55 years and older, mostly in developing countries.

The daily polypill in this trial is a combination of hydrochlorothiazide 25 mg, atenolol 100 mg, ramipril 10 mg, and simvastatin 40 mg; aspirin was given at 75 mg daily and vitamin D at 60,000 IU monthly.

The participants are followed for a primary end point composed of major CV disease, HF, resuscitated cardiac arrest, or ischemia-driven revascularization for the polypill comparison; CV events or cancer for the aspirin comparison; and fracture risk for the vitamin D component of the trial.

In the Swedish Cardiopulmonary Bioimage Study (SCAPIS), presented third in the session, a random sample of adults from throughout Sweden, projected at about 30,000, underwent a 2-day evaluation for metabolic risk factors plus ultrasound and coronary and lung CT scans. The group has been followed for risks for myocardial infarction (MI), sudden death, and other cardiac diseases; and chronic obstructive pulmonary disease (COPD) and other lung disorders.
 

Late-Breaking Science 3. Saturday, November 14, 12:00 PM - 1:00 PM CST

The field may learn more mechanistically about MI associated with nonobstructed coronary arteries (MINOCA) than ever before from the Heart Attack Research Program-Imaging Study (HARP). The observational study is enrolling a projected 450 patients with suspected MI and ischemic symptoms who were referred for cardiac catheterization.

Their evaluation includes coronary optical coherence tomographic (OCT) scanning and cardiac magnetic resonance (CMR) imaging for evidence of coronary plaque disruption as the primary end point. The patients are to be followed for 10 years for a composite of death, unstable angina, stroke, recurrent MI, diagnostic or interventional catheterization, and cardiac hospitalization.

The major direct oral anticoagulant (DOAC) comparisons with warfarin in atrial fibrillation (AF) didn’t include many patients with prosthetic valve implants. In contrast, the RIVER trial enrolled 1005 adults with either persistent or paroxysmal AF and bioprosthetic mitral valves and assigned them to rivaroxaban 20 mg or the vitamin K antagonist.

The presentation will include the noninferiority primary outcome of major clinical events, which is stroke, transient ischemic attack (TIA), major bleeding, death from any cause, valve thrombosis, other systemic embolism, or HF hospitalization over 12 months.

This session also includes ALPHEUS, a trial pitting ticagrelor (Brilinta/Brilique, AstraZeneca) against mainstay clopidogrel in a setting that is mostly uncharted for such comparisons, elective percutaneous coronary intervention (PCI).

About 1900 patients with stable coronary disease were randomly assigned to a month of treatment with either agent on top of continuous aspirin. The primary end point is PCI-related MI or myocardial injury within 48 hours of the procedure.
 

Late-Breaking Science 4. Sunday, November 15, 9:00 AM - 10:00 AM CST

The Self-Assessment Method for Statin Side-effects Or Nocebo (SAMSON) trial may be one of the AHA 2020 frontrunners for early buzz and anticipation. So it’s with some irony that it’s also among the smallest of the LBS studies, at 60 patients, which was nonetheless considered sufficient due to its unusual design.

SAMSON is the latest and perhaps most rigorous attempt to clarify whether symptoms, especially muscle pain or discomfort, attributed to statins by many patients are pharmacologic in origin or, rather, a nocebo effect from negative expectations about statin side effects.

The study patients, all of whom had previously halted statins because of side effects, were assigned to follow three separate regimens, each for month, in a randomized order; they did that four times, for a total of 12 months. The regimens consisted of atorvastatin 20 mg daily, a placebo, or neither.

Patients kept daily logs of any perceived side effects. Parity between side effects experienced on the statin and the placebo would point to a nocebo effect, whereas a significant excess on atorvastatin would suggest they are direct drug effects.

The session also features two randomized trials each on a unique omega-3 fatty acid preparation for either secondary prevention or high-risk primary prevention, in both cases compared with a corn-oil placebo.

The Omega-3 Fatty Acids in Elderly Patients with Myocardial Infarction (OMEMI) trial randomly assigned more than 1000 elderly post-MI patients to take Pikasol (Orkla Care) at 1.8 g EPA and DHA per day or the placebo. It looked for all-cause mortality, nonfatal MI, stroke, revascularization, or hospitalization for new or worsened HF over 24 months.

The STRENGTH trial, with a planned enrollment of about 13,000 high-vascular-risk patients, looked primarily at the effect of daily treatment with Epanova (AstraZeneca), which also contains DHA and EPA, on the composite of CV death, nonfatal MI or stroke, coronary revascularization, and hospitalization for unstable angina. The trial was halted early for low likelihood of benefit, AstraZeneca announced in January of this year.
 

Late-Breaking Science 5. Sunday, November 15, 7:15 PM - 8:30 PM CST

Slated for the session is the primary analysis of the PIONEER 3 trial, conducted in the United States, Europe, and Japan. It compared the BuMA Supreme biodegradable drug-coated stent (SinoMed) with the durable Xience (Abbott Vascular) and Promus (Boston Scientific) drug-eluting stents. The trial followed more than 1600 patients treated for chronic stable angina or acute coronary syndrome (ACS) for the 1-year composite of cardiac death, target-vessel-related MI, and clinically driven target-lesion revascularization.
 

Late-Breaking Science 6. Monday, November 16, 9:00 AM - 10:00 AM CST

The EARLY-AF trial enrolled 303 patients with symptomatic paroxysmal or persistent AF suitable for catheter ablation, assigning them to pulmonary vein isolation (PVI) by cryoablation using the Arctic Front (Medtronic) system or antiarrhythmic drug therapy for rhythm control. The primary end point is time to recurrence of AF, atrial flutter, or atrial tachycardia, whether symptomatic or asymptomatic, as determined by implantable loop recorder. Patients will also be followed for symptoms and arrhythmia burden.

Also in the session, the SEARCH-AF study randomized almost 400 patients undergoing cardiac surgery who were engaged subacutely with one of two commercial portable cardiac rhythm monitoring devices (CardioSTAT, Icentia; or SEEQ, Medtronic) or, alternatively, to receive usual postoperative care

The patients, considered to be at high risk for stroke with no history of AF, were followed for the primary end point of cumulative burden of AF or atrial flutter exceeding 6 minutes or documentation of either arrhythmia by 12-lead ECG within 30 days.

Two other studies in the session look at different approaches to AF screening, one using a handheld ECG monitor in the primary care setting and the other wearable monitors in the form of a patch or wristband. The VITAL-AF presentation is titled “Screening for Atrial Fibrillation in Older Adults at Primary Care Visits Using Single Lead Electrocardiograms.” The other presentation, on the study mSToPS, is called “Three-Year Clinical Outcomes in a Nationwide, Randomized, Pragmatic Clinical Trial of Atrial Fibrillation Screening — Mhealth Screening to Prevent Strokes.”
 

Late-Breaking Science 7. Monday, November 16, 7:00 PM - 8:30 PM CST

In the randomized FIDELIO-DKD trial with more than 5700 patients with type 2 diabetes and associated kidney disease, those assigned to the novel mineralocorticoid receptor antagonist (MRA) finerenone (Bayer) showed an 18% drop in risk for adverse renal events, including death from renal causes (P = .001), over a median of 2.6 years. That primary outcome was previously presented in detail at a nephrology meeting and published in the New England Journal of Medicine in October.

Patients on the MRA showed a similar reduction in a composite CV-event end point, it was also reported at that time. A follow-up presentation at the AHA sessions promises to dive deeper into the trial’s CV outcomes.

In the RAPID-CTCA study, slated next for the session, 1749 patients with suspected or confirmed intermediate-risk ACS were randomly assigned to undergo computed tomographic coronary angiography (CTCA) for guiding treatment decisions or a standard-of-care strategy. It followed patients for the primary end point of death or nonfatal MI over 1 year.

Rilonacept (Arcalyst, Kiniksa/Regeneron) is an interleukin-1α and -1β inhibitor used in several autoinflammatory diseases that went unsuccessfully before regulators for the treatment of gout. The RHAPSODY trial has now explored its use against recurrent pericarditis in a randomized trial that entered 86 patients 12 years and older who had previously experienced at least three episodes.

In top-line results reported to investors in June, patients assigned to receive the drug instead of placebo in weekly injections showed a 96% drop in risk for pericarditis recurrence and “no or minimal pain” on more than 90% of days in the trial. A full presentation is expected during this LBS session.

Also on the schedule is the THALES study, which led the US Food and Drug Administration (FDA) to expand indications for ticagrelor to include stroke prevention in patients with a history of acute ischemic stroke or high-risk TIA based on the trial’s primary results published in July.

In THALES, more than 11,000 patients with mild to moderate acute noncardiogenic ischemic stroke or TIA were randomly assigned within 24 hours to start on daily aspirin with or without ticagrelor given as a 180 mg loading dose followed by 90 mg twice daily for 30 days.

At the end of a month, it was reported, those on dual antiplatelet therapy showed a 17% risk reduction (P = .02) for the primary end point of stroke or death, at the cost of a slight but significant increase in “severe” bleeding (0.5% vs 0.1%; P = .001).

The session is to conclude with two related studies that fell victim in part to the COVID-19 pandemic, both of which explored sotagliflozin (Zynquista, Sanofi/Lexicon), an inhibitor of both sodium-glucose cotransporters 1 and 2 (SGLT1 and SGLT2, respectively) in patients with type 2 diabetes.

SOLOIST-WHF had entered 1222 such patients hospitalized with urgent or worsening HF at 466 centers and randomly assigned them to receive sotagliflozin or placebo; they were followed for the composite of CV death or HF events. SCORED reached an enrollment of 10,584 patients with diabetes and chronic kidney disease at 754 hospitals, following them for the same primary end point.

Lexicon announced in March that the trials would be “closed out early” because of the unavailability of funding “together with uncertainties relating to the COVID-19 pandemic on the trials.” The LBS presentation is expected to include analyses of available data; SOLOIST-WHF launched in summer 2018 and SCORED began in November 2017.
 

Late-Breaking Science 8. Tuesday, November 17, 9:00 AM - 10:00 AM CST

Most of this LBS session is devoted to the AHA COVID-19 Cardiovascular Disease registry, which is looking at the hospital journey, clinical course, and outcomes of patients hospitalized with SARS-CoV-2 infections at centers participating in the organization’s Get With The Guidelines (GWTG) quality-improvement program. As of September, the registry included data from more than 15,000 patients.

Scheduled presentations include a summary of the registry’s design and initial results; an analysis of racial and ethnic variation in therapy and clinical outcomes; an exploration of how body mass index influenced outcomes, including death, use of mechanical ventilation, and cardiovascular end points, in patients with COVID-19; and a deep dive into the relation between CV disease and clinical outcomes in the cohort.

The last of this LBS block’s five talks will cover the randomized Influenza Vaccine to Effectively Stop Cardio Thoracic Events and Decompensated Heart Failure (INVESTED) trial, which compared vaccination with high-dose trivalent influenza vaccine or a standard-dose quadrivalent vaccine in 5388 adults with a history of hospitalization for either MI or HF. Patients were required to have at least one other CV risk factor, such as older age, reduced left ventricular ejection fraction, or diabetes.

INVESTED tracked the patients at 190 centers across an initial pilot flu season and three subsequent flu seasons for the primary end point of death from any cause or cardiopulmonary hospitalization.

The trial is one of at least three that have been looking at the effect of flu vaccination on cardiovascular outcomes; results from the other two — IAMI, with more than 2500 participants, and RCT-IVVE, with an enrollment of 4871 — are planned for presentation in 2021, theheart.org | Medscape Cardiology recently reported.
 

Late-Breaking Science 9. Tuesday, November 17, 12:00 PM - 1:00 PM CST

The conference’s concluding LBS session features three studies that relied on technologic strategies for modifying patient compliance and other care behaviors and one that used human-centered design principles to develop a group-care model aimed improving the management of diabetes, hypertension, and other noncommunicable diseases in economically disadvantaged regions of Kenya.

The EPIC-HF trial tested a strategy for improving HFrEF medication-plan engagement by use of a video and documents delivered to patients several times by email or text prior to their follow-up clinic appointments. The strategy was compared with usual care for its effect on HF-medication optimization over 1 month and 1 year in a total of 306 patients.

Following EPIC-HF on the schedule is the MYROAD trial, looking at the efficacy of discharge instructions provided to patients with acute HF as an audio recording that they and their physicians could replay on demand, the idea being to increase adherence to the instructions. The trial’s 1073 patients were assigned to the novel strategy or usual care and followed for HF rehospitalization within 30 days.

MYROAD is to be followed by a presentation entitled “Digital Care Transformation: One-Year Report of >5,000 Patients Enrolled in a Remote Algorithm-Based CV Risk Management Program to Achieve Optimal Lipid and Hypertension Control.”

Rounding out the LBS session: the Bridging Income Generation With Group Integrated Care (BIGPIC) program, a pilot study that developed and executed “a healthcare delivery model targeting health behaviors, medication adherence, and financial barriers to accessing healthcare” in four rural counties in Kenya.

The model features locally developed plans, tailored for regional needs, that are said to “combine the benefits of microfinance with the peer support available through group medical care to enhance management of hypertension and diabetes.” The microfinance component is aimed at improving household economies to alleviate the financial burden of care and clinic attendance, and for the health effects of improved quality of life.

The study randomized 2890 adults with diabetes or prediabetes to one of four groups: usual care plus microfinance group support, group medical visits only or combined with microfinance group support, or usual care only. They were followed for changes in systolic blood pressure and CV-risk score over 12 months.

Lloyd-Jones and Fauci declared no conflicts.

This article first appeared on Medscape.com.

Cardiologists are already old hands at virtual meetings this year and are fast becoming experts on Zoom and other teleconferencing platforms, if not on how to unmute their microphones.

With expectations perhaps elevated and the new communications genre’s novelty on the wane, the American Heart Association (AHA) Scientific Sessions 2020 has a chance to both innovate with familiar formats and captivate with the field’s latest research findings.

Although the virtual AHA 2020 might not satisfy longings for face-to-face networking, shop talk, or kidding around over coffee, it will feature many traditional elements of the live conferences adapted for ear buds and small screens. They include late-breaking science (LBS) presentations and panel discussions, poster and live oral abstract presentations, meet-the-trialist talks, fireside-chat discussion forums, early career events, and satellite symposia.

The event may well hold lessons for future iterations of AHA Scientific Sessions in the postpandemic world, which some foresee as, potentially, an amalgam of the time-honored live format and a robust, complementary online presence.

Late-Breaking Science 1. Friday, November 13, 10:30 AM - 11:30 AM CST

The LBS sessions launch with the GALACTIC-HF trial, which — the world recently learned — may expand the burgeoning list of meds shown to improve clinical outcomes in chronic heart failure (HF) with reduced ejection fraction (HFrEF).

In cursory top-line results announced last month, those in the trial of more than 8000 patients who were randomly assigned to receive omecamtiv mecarbil (Amgen/Cytokinetics/Servier) showed a slight but significant benefit for the primary end point of cardiovascular (CV) death or HF events. The hazard ratio (HR), compared with standard care, was 0.92 (95% CI, 0.86 - 0.99; P = .025), noted a press release from Amgen.

Among the announcement’s few other details was a short take on safety outcomes: no difference in risk for “adverse events, including major ischemic cardiac events,” between the active and control groups. The presentation is sure to provide further insights and caveats, if any, along with other information crucial to the study’s interpretation.

Next on the schedule is the closely watched AFFIRM-AHF, billed as the first major outcomes trial of iron administration to iron-deficient patients with acute HF. It randomly assigned more than 1000 such patients to receive IV ferric carboxymaltose or a placebo. The first dose was given in-hospital and subsequent doses at home for 24 weeks or until patients were no longer iron deficient. They were followed to 1 year for the primary end point of recurrent HF hospitalizations or CV death.

The session wraps with the VITAL Rhythm trial, a substudy of the doubly randomized VITAL trial that explored the effects of vitamin D and omega-3 fatty acid supplementation on CV and cancer risk in more than 25,000 patients in the community. The substudy explored the effects of two active therapies, a preparation of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (Omacor, Reliant Pharmaceuticals) or vitamin D3 supplements, on new-onset atrial fibrillation (AF) as the primary end point; it also looked at risk for sudden death.
 

Late-Breaking Science 2. Friday, November 13, 12:00 PM - 1:00 PM CST

Dominating the session in two presentations, the (TIPS)-3 trial explored a polypill primary-prevention strategy and daily aspirin with vitamin D supplementation in three separate placebo-controlled comparisons in more than 5700 “intermediate risk” participants 55 years and older, mostly in developing countries.

The daily polypill in this trial is a combination of hydrochlorothiazide 25 mg, atenolol 100 mg, ramipril 10 mg, and simvastatin 40 mg; aspirin was given at 75 mg daily and vitamin D at 60,000 IU monthly.

The participants are followed for a primary end point composed of major CV disease, HF, resuscitated cardiac arrest, or ischemia-driven revascularization for the polypill comparison; CV events or cancer for the aspirin comparison; and fracture risk for the vitamin D component of the trial.

In the Swedish Cardiopulmonary Bioimage Study (SCAPIS), presented third in the session, a random sample of adults from throughout Sweden, projected at about 30,000, underwent a 2-day evaluation for metabolic risk factors plus ultrasound and coronary and lung CT scans. The group has been followed for risks for myocardial infarction (MI), sudden death, and other cardiac diseases; and chronic obstructive pulmonary disease (COPD) and other lung disorders.
 

Late-Breaking Science 3. Saturday, November 14, 12:00 PM - 1:00 PM CST

The field may learn more mechanistically about MI associated with nonobstructed coronary arteries (MINOCA) than ever before from the Heart Attack Research Program-Imaging Study (HARP). The observational study is enrolling a projected 450 patients with suspected MI and ischemic symptoms who were referred for cardiac catheterization.

Their evaluation includes coronary optical coherence tomographic (OCT) scanning and cardiac magnetic resonance (CMR) imaging for evidence of coronary plaque disruption as the primary end point. The patients are to be followed for 10 years for a composite of death, unstable angina, stroke, recurrent MI, diagnostic or interventional catheterization, and cardiac hospitalization.

The major direct oral anticoagulant (DOAC) comparisons with warfarin in atrial fibrillation (AF) didn’t include many patients with prosthetic valve implants. In contrast, the RIVER trial enrolled 1005 adults with either persistent or paroxysmal AF and bioprosthetic mitral valves and assigned them to rivaroxaban 20 mg or the vitamin K antagonist.

The presentation will include the noninferiority primary outcome of major clinical events, which is stroke, transient ischemic attack (TIA), major bleeding, death from any cause, valve thrombosis, other systemic embolism, or HF hospitalization over 12 months.

This session also includes ALPHEUS, a trial pitting ticagrelor (Brilinta/Brilique, AstraZeneca) against mainstay clopidogrel in a setting that is mostly uncharted for such comparisons, elective percutaneous coronary intervention (PCI).

About 1900 patients with stable coronary disease were randomly assigned to a month of treatment with either agent on top of continuous aspirin. The primary end point is PCI-related MI or myocardial injury within 48 hours of the procedure.
 

Late-Breaking Science 4. Sunday, November 15, 9:00 AM - 10:00 AM CST

The Self-Assessment Method for Statin Side-effects Or Nocebo (SAMSON) trial may be one of the AHA 2020 frontrunners for early buzz and anticipation. So it’s with some irony that it’s also among the smallest of the LBS studies, at 60 patients, which was nonetheless considered sufficient due to its unusual design.

SAMSON is the latest and perhaps most rigorous attempt to clarify whether symptoms, especially muscle pain or discomfort, attributed to statins by many patients are pharmacologic in origin or, rather, a nocebo effect from negative expectations about statin side effects.

The study patients, all of whom had previously halted statins because of side effects, were assigned to follow three separate regimens, each for month, in a randomized order; they did that four times, for a total of 12 months. The regimens consisted of atorvastatin 20 mg daily, a placebo, or neither.

Patients kept daily logs of any perceived side effects. Parity between side effects experienced on the statin and the placebo would point to a nocebo effect, whereas a significant excess on atorvastatin would suggest they are direct drug effects.

The session also features two randomized trials each on a unique omega-3 fatty acid preparation for either secondary prevention or high-risk primary prevention, in both cases compared with a corn-oil placebo.

The Omega-3 Fatty Acids in Elderly Patients with Myocardial Infarction (OMEMI) trial randomly assigned more than 1000 elderly post-MI patients to take Pikasol (Orkla Care) at 1.8 g EPA and DHA per day or the placebo. It looked for all-cause mortality, nonfatal MI, stroke, revascularization, or hospitalization for new or worsened HF over 24 months.

The STRENGTH trial, with a planned enrollment of about 13,000 high-vascular-risk patients, looked primarily at the effect of daily treatment with Epanova (AstraZeneca), which also contains DHA and EPA, on the composite of CV death, nonfatal MI or stroke, coronary revascularization, and hospitalization for unstable angina. The trial was halted early for low likelihood of benefit, AstraZeneca announced in January of this year.
 

Late-Breaking Science 5. Sunday, November 15, 7:15 PM - 8:30 PM CST

Slated for the session is the primary analysis of the PIONEER 3 trial, conducted in the United States, Europe, and Japan. It compared the BuMA Supreme biodegradable drug-coated stent (SinoMed) with the durable Xience (Abbott Vascular) and Promus (Boston Scientific) drug-eluting stents. The trial followed more than 1600 patients treated for chronic stable angina or acute coronary syndrome (ACS) for the 1-year composite of cardiac death, target-vessel-related MI, and clinically driven target-lesion revascularization.
 

Late-Breaking Science 6. Monday, November 16, 9:00 AM - 10:00 AM CST

The EARLY-AF trial enrolled 303 patients with symptomatic paroxysmal or persistent AF suitable for catheter ablation, assigning them to pulmonary vein isolation (PVI) by cryoablation using the Arctic Front (Medtronic) system or antiarrhythmic drug therapy for rhythm control. The primary end point is time to recurrence of AF, atrial flutter, or atrial tachycardia, whether symptomatic or asymptomatic, as determined by implantable loop recorder. Patients will also be followed for symptoms and arrhythmia burden.

Also in the session, the SEARCH-AF study randomized almost 400 patients undergoing cardiac surgery who were engaged subacutely with one of two commercial portable cardiac rhythm monitoring devices (CardioSTAT, Icentia; or SEEQ, Medtronic) or, alternatively, to receive usual postoperative care

The patients, considered to be at high risk for stroke with no history of AF, were followed for the primary end point of cumulative burden of AF or atrial flutter exceeding 6 minutes or documentation of either arrhythmia by 12-lead ECG within 30 days.

Two other studies in the session look at different approaches to AF screening, one using a handheld ECG monitor in the primary care setting and the other wearable monitors in the form of a patch or wristband. The VITAL-AF presentation is titled “Screening for Atrial Fibrillation in Older Adults at Primary Care Visits Using Single Lead Electrocardiograms.” The other presentation, on the study mSToPS, is called “Three-Year Clinical Outcomes in a Nationwide, Randomized, Pragmatic Clinical Trial of Atrial Fibrillation Screening — Mhealth Screening to Prevent Strokes.”
 

Late-Breaking Science 7. Monday, November 16, 7:00 PM - 8:30 PM CST

In the randomized FIDELIO-DKD trial with more than 5700 patients with type 2 diabetes and associated kidney disease, those assigned to the novel mineralocorticoid receptor antagonist (MRA) finerenone (Bayer) showed an 18% drop in risk for adverse renal events, including death from renal causes (P = .001), over a median of 2.6 years. That primary outcome was previously presented in detail at a nephrology meeting and published in the New England Journal of Medicine in October.

Patients on the MRA showed a similar reduction in a composite CV-event end point, it was also reported at that time. A follow-up presentation at the AHA sessions promises to dive deeper into the trial’s CV outcomes.

In the RAPID-CTCA study, slated next for the session, 1749 patients with suspected or confirmed intermediate-risk ACS were randomly assigned to undergo computed tomographic coronary angiography (CTCA) for guiding treatment decisions or a standard-of-care strategy. It followed patients for the primary end point of death or nonfatal MI over 1 year.

Rilonacept (Arcalyst, Kiniksa/Regeneron) is an interleukin-1α and -1β inhibitor used in several autoinflammatory diseases that went unsuccessfully before regulators for the treatment of gout. The RHAPSODY trial has now explored its use against recurrent pericarditis in a randomized trial that entered 86 patients 12 years and older who had previously experienced at least three episodes.

In top-line results reported to investors in June, patients assigned to receive the drug instead of placebo in weekly injections showed a 96% drop in risk for pericarditis recurrence and “no or minimal pain” on more than 90% of days in the trial. A full presentation is expected during this LBS session.

Also on the schedule is the THALES study, which led the US Food and Drug Administration (FDA) to expand indications for ticagrelor to include stroke prevention in patients with a history of acute ischemic stroke or high-risk TIA based on the trial’s primary results published in July.

In THALES, more than 11,000 patients with mild to moderate acute noncardiogenic ischemic stroke or TIA were randomly assigned within 24 hours to start on daily aspirin with or without ticagrelor given as a 180 mg loading dose followed by 90 mg twice daily for 30 days.

At the end of a month, it was reported, those on dual antiplatelet therapy showed a 17% risk reduction (P = .02) for the primary end point of stroke or death, at the cost of a slight but significant increase in “severe” bleeding (0.5% vs 0.1%; P = .001).

The session is to conclude with two related studies that fell victim in part to the COVID-19 pandemic, both of which explored sotagliflozin (Zynquista, Sanofi/Lexicon), an inhibitor of both sodium-glucose cotransporters 1 and 2 (SGLT1 and SGLT2, respectively) in patients with type 2 diabetes.

SOLOIST-WHF had entered 1222 such patients hospitalized with urgent or worsening HF at 466 centers and randomly assigned them to receive sotagliflozin or placebo; they were followed for the composite of CV death or HF events. SCORED reached an enrollment of 10,584 patients with diabetes and chronic kidney disease at 754 hospitals, following them for the same primary end point.

Lexicon announced in March that the trials would be “closed out early” because of the unavailability of funding “together with uncertainties relating to the COVID-19 pandemic on the trials.” The LBS presentation is expected to include analyses of available data; SOLOIST-WHF launched in summer 2018 and SCORED began in November 2017.
 

Late-Breaking Science 8. Tuesday, November 17, 9:00 AM - 10:00 AM CST

Most of this LBS session is devoted to the AHA COVID-19 Cardiovascular Disease registry, which is looking at the hospital journey, clinical course, and outcomes of patients hospitalized with SARS-CoV-2 infections at centers participating in the organization’s Get With The Guidelines (GWTG) quality-improvement program. As of September, the registry included data from more than 15,000 patients.

Scheduled presentations include a summary of the registry’s design and initial results; an analysis of racial and ethnic variation in therapy and clinical outcomes; an exploration of how body mass index influenced outcomes, including death, use of mechanical ventilation, and cardiovascular end points, in patients with COVID-19; and a deep dive into the relation between CV disease and clinical outcomes in the cohort.

The last of this LBS block’s five talks will cover the randomized Influenza Vaccine to Effectively Stop Cardio Thoracic Events and Decompensated Heart Failure (INVESTED) trial, which compared vaccination with high-dose trivalent influenza vaccine or a standard-dose quadrivalent vaccine in 5388 adults with a history of hospitalization for either MI or HF. Patients were required to have at least one other CV risk factor, such as older age, reduced left ventricular ejection fraction, or diabetes.

INVESTED tracked the patients at 190 centers across an initial pilot flu season and three subsequent flu seasons for the primary end point of death from any cause or cardiopulmonary hospitalization.

The trial is one of at least three that have been looking at the effect of flu vaccination on cardiovascular outcomes; results from the other two — IAMI, with more than 2500 participants, and RCT-IVVE, with an enrollment of 4871 — are planned for presentation in 2021, theheart.org | Medscape Cardiology recently reported.
 

Late-Breaking Science 9. Tuesday, November 17, 12:00 PM - 1:00 PM CST

The conference’s concluding LBS session features three studies that relied on technologic strategies for modifying patient compliance and other care behaviors and one that used human-centered design principles to develop a group-care model aimed improving the management of diabetes, hypertension, and other noncommunicable diseases in economically disadvantaged regions of Kenya.

The EPIC-HF trial tested a strategy for improving HFrEF medication-plan engagement by use of a video and documents delivered to patients several times by email or text prior to their follow-up clinic appointments. The strategy was compared with usual care for its effect on HF-medication optimization over 1 month and 1 year in a total of 306 patients.

Following EPIC-HF on the schedule is the MYROAD trial, looking at the efficacy of discharge instructions provided to patients with acute HF as an audio recording that they and their physicians could replay on demand, the idea being to increase adherence to the instructions. The trial’s 1073 patients were assigned to the novel strategy or usual care and followed for HF rehospitalization within 30 days.

MYROAD is to be followed by a presentation entitled “Digital Care Transformation: One-Year Report of >5,000 Patients Enrolled in a Remote Algorithm-Based CV Risk Management Program to Achieve Optimal Lipid and Hypertension Control.”

Rounding out the LBS session: the Bridging Income Generation With Group Integrated Care (BIGPIC) program, a pilot study that developed and executed “a healthcare delivery model targeting health behaviors, medication adherence, and financial barriers to accessing healthcare” in four rural counties in Kenya.

The model features locally developed plans, tailored for regional needs, that are said to “combine the benefits of microfinance with the peer support available through group medical care to enhance management of hypertension and diabetes.” The microfinance component is aimed at improving household economies to alleviate the financial burden of care and clinic attendance, and for the health effects of improved quality of life.

The study randomized 2890 adults with diabetes or prediabetes to one of four groups: usual care plus microfinance group support, group medical visits only or combined with microfinance group support, or usual care only. They were followed for changes in systolic blood pressure and CV-risk score over 12 months.

Lloyd-Jones and Fauci declared no conflicts.

This article first appeared on Medscape.com.

Cardiologists are already old hands at virtual meetings this year and are fast becoming experts on Zoom and other teleconferencing platforms, if not on how to unmute their microphones.

With expectations perhaps elevated and the new communications genre’s novelty on the wane, the American Heart Association (AHA) Scientific Sessions 2020 has a chance to both innovate with familiar formats and captivate with the field’s latest research findings.

Although the virtual AHA 2020 might not satisfy longings for face-to-face networking, shop talk, or kidding around over coffee, it will feature many traditional elements of the live conferences adapted for ear buds and small screens. They include late-breaking science (LBS) presentations and panel discussions, poster and live oral abstract presentations, meet-the-trialist talks, fireside-chat discussion forums, early career events, and satellite symposia.

The event may well hold lessons for future iterations of AHA Scientific Sessions in the postpandemic world, which some foresee as, potentially, an amalgam of the time-honored live format and a robust, complementary online presence.

Late-Breaking Science 1. Friday, November 13, 10:30 AM - 11:30 AM CST

The LBS sessions launch with the GALACTIC-HF trial, which — the world recently learned — may expand the burgeoning list of meds shown to improve clinical outcomes in chronic heart failure (HF) with reduced ejection fraction (HFrEF).

In cursory top-line results announced last month, those in the trial of more than 8000 patients who were randomly assigned to receive omecamtiv mecarbil (Amgen/Cytokinetics/Servier) showed a slight but significant benefit for the primary end point of cardiovascular (CV) death or HF events. The hazard ratio (HR), compared with standard care, was 0.92 (95% CI, 0.86 - 0.99; P = .025), noted a press release from Amgen.

Among the announcement’s few other details was a short take on safety outcomes: no difference in risk for “adverse events, including major ischemic cardiac events,” between the active and control groups. The presentation is sure to provide further insights and caveats, if any, along with other information crucial to the study’s interpretation.

Next on the schedule is the closely watched AFFIRM-AHF, billed as the first major outcomes trial of iron administration to iron-deficient patients with acute HF. It randomly assigned more than 1000 such patients to receive IV ferric carboxymaltose or a placebo. The first dose was given in-hospital and subsequent doses at home for 24 weeks or until patients were no longer iron deficient. They were followed to 1 year for the primary end point of recurrent HF hospitalizations or CV death.

The session wraps with the VITAL Rhythm trial, a substudy of the doubly randomized VITAL trial that explored the effects of vitamin D and omega-3 fatty acid supplementation on CV and cancer risk in more than 25,000 patients in the community. The substudy explored the effects of two active therapies, a preparation of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (Omacor, Reliant Pharmaceuticals) or vitamin D3 supplements, on new-onset atrial fibrillation (AF) as the primary end point; it also looked at risk for sudden death.
 

Late-Breaking Science 2. Friday, November 13, 12:00 PM - 1:00 PM CST

Dominating the session in two presentations, the (TIPS)-3 trial explored a polypill primary-prevention strategy and daily aspirin with vitamin D supplementation in three separate placebo-controlled comparisons in more than 5700 “intermediate risk” participants 55 years and older, mostly in developing countries.

The daily polypill in this trial is a combination of hydrochlorothiazide 25 mg, atenolol 100 mg, ramipril 10 mg, and simvastatin 40 mg; aspirin was given at 75 mg daily and vitamin D at 60,000 IU monthly.

The participants are followed for a primary end point composed of major CV disease, HF, resuscitated cardiac arrest, or ischemia-driven revascularization for the polypill comparison; CV events or cancer for the aspirin comparison; and fracture risk for the vitamin D component of the trial.

In the Swedish Cardiopulmonary Bioimage Study (SCAPIS), presented third in the session, a random sample of adults from throughout Sweden, projected at about 30,000, underwent a 2-day evaluation for metabolic risk factors plus ultrasound and coronary and lung CT scans. The group has been followed for risks for myocardial infarction (MI), sudden death, and other cardiac diseases; and chronic obstructive pulmonary disease (COPD) and other lung disorders.
 

Late-Breaking Science 3. Saturday, November 14, 12:00 PM - 1:00 PM CST

The field may learn more mechanistically about MI associated with nonobstructed coronary arteries (MINOCA) than ever before from the Heart Attack Research Program-Imaging Study (HARP). The observational study is enrolling a projected 450 patients with suspected MI and ischemic symptoms who were referred for cardiac catheterization.

Their evaluation includes coronary optical coherence tomographic (OCT) scanning and cardiac magnetic resonance (CMR) imaging for evidence of coronary plaque disruption as the primary end point. The patients are to be followed for 10 years for a composite of death, unstable angina, stroke, recurrent MI, diagnostic or interventional catheterization, and cardiac hospitalization.

The major direct oral anticoagulant (DOAC) comparisons with warfarin in atrial fibrillation (AF) didn’t include many patients with prosthetic valve implants. In contrast, the RIVER trial enrolled 1005 adults with either persistent or paroxysmal AF and bioprosthetic mitral valves and assigned them to rivaroxaban 20 mg or the vitamin K antagonist.

The presentation will include the noninferiority primary outcome of major clinical events, which is stroke, transient ischemic attack (TIA), major bleeding, death from any cause, valve thrombosis, other systemic embolism, or HF hospitalization over 12 months.

This session also includes ALPHEUS, a trial pitting ticagrelor (Brilinta/Brilique, AstraZeneca) against mainstay clopidogrel in a setting that is mostly uncharted for such comparisons, elective percutaneous coronary intervention (PCI).

About 1900 patients with stable coronary disease were randomly assigned to a month of treatment with either agent on top of continuous aspirin. The primary end point is PCI-related MI or myocardial injury within 48 hours of the procedure.
 

Late-Breaking Science 4. Sunday, November 15, 9:00 AM - 10:00 AM CST

The Self-Assessment Method for Statin Side-effects Or Nocebo (SAMSON) trial may be one of the AHA 2020 frontrunners for early buzz and anticipation. So it’s with some irony that it’s also among the smallest of the LBS studies, at 60 patients, which was nonetheless considered sufficient due to its unusual design.

SAMSON is the latest and perhaps most rigorous attempt to clarify whether symptoms, especially muscle pain or discomfort, attributed to statins by many patients are pharmacologic in origin or, rather, a nocebo effect from negative expectations about statin side effects.

The study patients, all of whom had previously halted statins because of side effects, were assigned to follow three separate regimens, each for month, in a randomized order; they did that four times, for a total of 12 months. The regimens consisted of atorvastatin 20 mg daily, a placebo, or neither.

Patients kept daily logs of any perceived side effects. Parity between side effects experienced on the statin and the placebo would point to a nocebo effect, whereas a significant excess on atorvastatin would suggest they are direct drug effects.

The session also features two randomized trials each on a unique omega-3 fatty acid preparation for either secondary prevention or high-risk primary prevention, in both cases compared with a corn-oil placebo.

The Omega-3 Fatty Acids in Elderly Patients with Myocardial Infarction (OMEMI) trial randomly assigned more than 1000 elderly post-MI patients to take Pikasol (Orkla Care) at 1.8 g EPA and DHA per day or the placebo. It looked for all-cause mortality, nonfatal MI, stroke, revascularization, or hospitalization for new or worsened HF over 24 months.

The STRENGTH trial, with a planned enrollment of about 13,000 high-vascular-risk patients, looked primarily at the effect of daily treatment with Epanova (AstraZeneca), which also contains DHA and EPA, on the composite of CV death, nonfatal MI or stroke, coronary revascularization, and hospitalization for unstable angina. The trial was halted early for low likelihood of benefit, AstraZeneca announced in January of this year.
 

Late-Breaking Science 5. Sunday, November 15, 7:15 PM - 8:30 PM CST

Slated for the session is the primary analysis of the PIONEER 3 trial, conducted in the United States, Europe, and Japan. It compared the BuMA Supreme biodegradable drug-coated stent (SinoMed) with the durable Xience (Abbott Vascular) and Promus (Boston Scientific) drug-eluting stents. The trial followed more than 1600 patients treated for chronic stable angina or acute coronary syndrome (ACS) for the 1-year composite of cardiac death, target-vessel-related MI, and clinically driven target-lesion revascularization.
 

Late-Breaking Science 6. Monday, November 16, 9:00 AM - 10:00 AM CST

The EARLY-AF trial enrolled 303 patients with symptomatic paroxysmal or persistent AF suitable for catheter ablation, assigning them to pulmonary vein isolation (PVI) by cryoablation using the Arctic Front (Medtronic) system or antiarrhythmic drug therapy for rhythm control. The primary end point is time to recurrence of AF, atrial flutter, or atrial tachycardia, whether symptomatic or asymptomatic, as determined by implantable loop recorder. Patients will also be followed for symptoms and arrhythmia burden.

Also in the session, the SEARCH-AF study randomized almost 400 patients undergoing cardiac surgery who were engaged subacutely with one of two commercial portable cardiac rhythm monitoring devices (CardioSTAT, Icentia; or SEEQ, Medtronic) or, alternatively, to receive usual postoperative care

The patients, considered to be at high risk for stroke with no history of AF, were followed for the primary end point of cumulative burden of AF or atrial flutter exceeding 6 minutes or documentation of either arrhythmia by 12-lead ECG within 30 days.

Two other studies in the session look at different approaches to AF screening, one using a handheld ECG monitor in the primary care setting and the other wearable monitors in the form of a patch or wristband. The VITAL-AF presentation is titled “Screening for Atrial Fibrillation in Older Adults at Primary Care Visits Using Single Lead Electrocardiograms.” The other presentation, on the study mSToPS, is called “Three-Year Clinical Outcomes in a Nationwide, Randomized, Pragmatic Clinical Trial of Atrial Fibrillation Screening — Mhealth Screening to Prevent Strokes.”
 

Late-Breaking Science 7. Monday, November 16, 7:00 PM - 8:30 PM CST

In the randomized FIDELIO-DKD trial with more than 5700 patients with type 2 diabetes and associated kidney disease, those assigned to the novel mineralocorticoid receptor antagonist (MRA) finerenone (Bayer) showed an 18% drop in risk for adverse renal events, including death from renal causes (P = .001), over a median of 2.6 years. That primary outcome was previously presented in detail at a nephrology meeting and published in the New England Journal of Medicine in October.

Patients on the MRA showed a similar reduction in a composite CV-event end point, it was also reported at that time. A follow-up presentation at the AHA sessions promises to dive deeper into the trial’s CV outcomes.

In the RAPID-CTCA study, slated next for the session, 1749 patients with suspected or confirmed intermediate-risk ACS were randomly assigned to undergo computed tomographic coronary angiography (CTCA) for guiding treatment decisions or a standard-of-care strategy. It followed patients for the primary end point of death or nonfatal MI over 1 year.

Rilonacept (Arcalyst, Kiniksa/Regeneron) is an interleukin-1α and -1β inhibitor used in several autoinflammatory diseases that went unsuccessfully before regulators for the treatment of gout. The RHAPSODY trial has now explored its use against recurrent pericarditis in a randomized trial that entered 86 patients 12 years and older who had previously experienced at least three episodes.

In top-line results reported to investors in June, patients assigned to receive the drug instead of placebo in weekly injections showed a 96% drop in risk for pericarditis recurrence and “no or minimal pain” on more than 90% of days in the trial. A full presentation is expected during this LBS session.

Also on the schedule is the THALES study, which led the US Food and Drug Administration (FDA) to expand indications for ticagrelor to include stroke prevention in patients with a history of acute ischemic stroke or high-risk TIA based on the trial’s primary results published in July.

In THALES, more than 11,000 patients with mild to moderate acute noncardiogenic ischemic stroke or TIA were randomly assigned within 24 hours to start on daily aspirin with or without ticagrelor given as a 180 mg loading dose followed by 90 mg twice daily for 30 days.

At the end of a month, it was reported, those on dual antiplatelet therapy showed a 17% risk reduction (P = .02) for the primary end point of stroke or death, at the cost of a slight but significant increase in “severe” bleeding (0.5% vs 0.1%; P = .001).

The session is to conclude with two related studies that fell victim in part to the COVID-19 pandemic, both of which explored sotagliflozin (Zynquista, Sanofi/Lexicon), an inhibitor of both sodium-glucose cotransporters 1 and 2 (SGLT1 and SGLT2, respectively) in patients with type 2 diabetes.

SOLOIST-WHF had entered 1222 such patients hospitalized with urgent or worsening HF at 466 centers and randomly assigned them to receive sotagliflozin or placebo; they were followed for the composite of CV death or HF events. SCORED reached an enrollment of 10,584 patients with diabetes and chronic kidney disease at 754 hospitals, following them for the same primary end point.

Lexicon announced in March that the trials would be “closed out early” because of the unavailability of funding “together with uncertainties relating to the COVID-19 pandemic on the trials.” The LBS presentation is expected to include analyses of available data; SOLOIST-WHF launched in summer 2018 and SCORED began in November 2017.
 

Late-Breaking Science 8. Tuesday, November 17, 9:00 AM - 10:00 AM CST

Most of this LBS session is devoted to the AHA COVID-19 Cardiovascular Disease registry, which is looking at the hospital journey, clinical course, and outcomes of patients hospitalized with SARS-CoV-2 infections at centers participating in the organization’s Get With The Guidelines (GWTG) quality-improvement program. As of September, the registry included data from more than 15,000 patients.

Scheduled presentations include a summary of the registry’s design and initial results; an analysis of racial and ethnic variation in therapy and clinical outcomes; an exploration of how body mass index influenced outcomes, including death, use of mechanical ventilation, and cardiovascular end points, in patients with COVID-19; and a deep dive into the relation between CV disease and clinical outcomes in the cohort.

The last of this LBS block’s five talks will cover the randomized Influenza Vaccine to Effectively Stop Cardio Thoracic Events and Decompensated Heart Failure (INVESTED) trial, which compared vaccination with high-dose trivalent influenza vaccine or a standard-dose quadrivalent vaccine in 5388 adults with a history of hospitalization for either MI or HF. Patients were required to have at least one other CV risk factor, such as older age, reduced left ventricular ejection fraction, or diabetes.

INVESTED tracked the patients at 190 centers across an initial pilot flu season and three subsequent flu seasons for the primary end point of death from any cause or cardiopulmonary hospitalization.

The trial is one of at least three that have been looking at the effect of flu vaccination on cardiovascular outcomes; results from the other two — IAMI, with more than 2500 participants, and RCT-IVVE, with an enrollment of 4871 — are planned for presentation in 2021, theheart.org | Medscape Cardiology recently reported.
 

Late-Breaking Science 9. Tuesday, November 17, 12:00 PM - 1:00 PM CST

The conference’s concluding LBS session features three studies that relied on technologic strategies for modifying patient compliance and other care behaviors and one that used human-centered design principles to develop a group-care model aimed improving the management of diabetes, hypertension, and other noncommunicable diseases in economically disadvantaged regions of Kenya.

The EPIC-HF trial tested a strategy for improving HFrEF medication-plan engagement by use of a video and documents delivered to patients several times by email or text prior to their follow-up clinic appointments. The strategy was compared with usual care for its effect on HF-medication optimization over 1 month and 1 year in a total of 306 patients.

Following EPIC-HF on the schedule is the MYROAD trial, looking at the efficacy of discharge instructions provided to patients with acute HF as an audio recording that they and their physicians could replay on demand, the idea being to increase adherence to the instructions. The trial’s 1073 patients were assigned to the novel strategy or usual care and followed for HF rehospitalization within 30 days.

MYROAD is to be followed by a presentation entitled “Digital Care Transformation: One-Year Report of >5,000 Patients Enrolled in a Remote Algorithm-Based CV Risk Management Program to Achieve Optimal Lipid and Hypertension Control.”

Rounding out the LBS session: the Bridging Income Generation With Group Integrated Care (BIGPIC) program, a pilot study that developed and executed “a healthcare delivery model targeting health behaviors, medication adherence, and financial barriers to accessing healthcare” in four rural counties in Kenya.

The model features locally developed plans, tailored for regional needs, that are said to “combine the benefits of microfinance with the peer support available through group medical care to enhance management of hypertension and diabetes.” The microfinance component is aimed at improving household economies to alleviate the financial burden of care and clinic attendance, and for the health effects of improved quality of life.

The study randomized 2890 adults with diabetes or prediabetes to one of four groups: usual care plus microfinance group support, group medical visits only or combined with microfinance group support, or usual care only. They were followed for changes in systolic blood pressure and CV-risk score over 12 months.

Lloyd-Jones and Fauci declared no conflicts.

This article first appeared on Medscape.com.

In order for percutaneous coronary intervention (PCI) to shine, compared with meds alone in patients with type-2 diabetes and stable coronary disease (CAD), it needs help from aggressive control of LDL cholesterol (LDL-C) levels, suggests a patient-level meta-analysis of three major randomized trials.

Performing PCI in such patients with diabetes conferred further benefit over optimal medical therapy (OMT) for major adverse cardiac or cerebrovascular events (MACCE) only among those whose LDL-C levels had been pushed below the guidelines-specified threshold of 70 mg/dL within 1 year.

At that level of LDL-C control, PCI, compared with the meds-alone strategy, was followed by a nearly 40% drop in 4-year risk for the composite endpoint, which consisted of death from any cause or nonfatal myocardial infarction (MI) or stroke.

Also for patients reaching a 1-year LDL-C of <70 mg/dL, the risk of MACCE was similar for those who had been assigned to coronary bypass surgery (CABG), compared with PCI. But that risk was significantly lower for the CABG group among those reaching LDL-C levels above that threshold.

“The strategy of revascularization with the LDL lowering, that’s the combination that seems to be a winner” in such patients with diabetes and stable CAD, lead author Michael E. Farkouh, MD, MSc, said in an interview.

If their LDL-C “stays above 70 mg/dL, they don’t really enjoy any benefit of PCI. It’s a message to our interventional community to really drive that LDL down,” said Dr. Farkouh, of the University of Toronto. “Not only with statins, but perhaps with PCSK9 inhibitors, ezetimibe, and other therapies to lower that LDL-C.”

The analysis, published Nov. 2 in the Journal of the American College of Cardiology, pooled more than 4,000 patients with diabetes and stable CAD randomized in the BARI 2D, FREEDOM, and COURAGE trials.

The new study adds a twist to an ongoing theme throughout some meta-analyses and clinical trials like ISCHEMIA since the results of COURAGE were unveiled 13 years ago. The latter trial famously saw no significant difference in death, MI, or stroke in patients with stable CAD assigned to OMT with or without PCI. That set off years of controversy about the relative merits of the revascularization and meds-only strategies in stable CAD that persists today.

But, Dr. Farkouh proposed, whether PCI improves clinical outcomes, compared with meds alone, at least in patients with diabetes, may be tied to the success of LDL-C-lowering therapies in reaching that goal, which in the current study was below 70 mg/dL.

“In this analysis of pooled data from the three major trials, we demonstrate that attaining that level of LDL-C at 1 year portends a better outcome for PCI” in patients with diabetes and stable CAD, he said.

The findings “probably need to be studied further, but it is compelling to think that if we can drive the LDL-C down by one year after the procedure, we have better outcomes with PCI,” compared with a meds-only strategy in patients with diabetes and stable CAD. “That really vindicates a lot of those who believe in PCI,” Dr. Farkouh said.

“What’s surprising to me is, if the patient has an LDL less than 70, why is it that there is a benefit of PCI, compared to medical therapy alone? Because they’re already so aggressively managed, you would think there shouldn’t be a benefit,” Sripal Bangalore, MD, MHA, New York University, said in an interview. “For me, that part is difficult to understand.”

The finding somewhat contradicts the results of ISCHEMIA, in which OMT – including LDL-C-lowering therapy – was considered more aggressive than usually managed in practice, Bangalore said. Yet the trial saw no outcomes difference between PCI and the more conservative approach, leading some to speculate that PCI may be a better choice when, for whatever reason, medical therapy isn’t optimal.

The observed superiority of PCI over meds-only at the lowest LDL-C levels is, according to Dr. Banagalore, “more likely because of residual confounding, given the fact that they’re combining three different trials, which are aimed to address different sets of questions.” He was an investigator with the FREEDOM and ISCHEMIA trials but isn’t associated with the current report.

The main message from this observational analysis is that “of course, we want to get the LDL as low as possible in these patients with demonstrated cardiovascular disease and diabetes,” Donald M. Lloyd-Jones, MD, ScM, Northwestern University, Chicago, said in an interview. “Every one of these patients should be shooting for as low an LDL as possible.”

Regardless of revascularization strategy, he said, “we have to get people on a high-intensity statin, or at least their maximally targeted dose, and have a careful and thoughtful conversation about whether they need additional lowering with, perhaps, ezetimibe, if they’re not below the thresholds we’d like to see them at, in this case, 70 mg/dL.”

Still, the current findings that the relative effects of PCI and CABG in these patients may vary by degree of LDL-C reduction “are interesting, but would have to be tested a little bit more directly,” said Dr. Lloyd-Jones, who is not affiliated with the analysis.

An accompanying editorial, which also acknowledges the study’s limitations, says its results “are relevant for clinical practice and may pave the way toward the generation of novel personalized medicine models that can optimize care of patients with type-2 diabetes.” 

They “support the concept of an individualized treatment strategy that accounts for a patient’s LDL-C level to estimate clinical outcomes and expected treatment effects after therapeutic interventions,” say the authors, led by Eliano P. Navarese, MD, PhD, Nicolaus Copernicus University, Bydgoszcz, Poland.

“For daily practice, these results also underscore the importance of follow-up LDL-C measurements, both as a risk stratifier and as an indicator for therapy adjustments,” they write, noting that “current guidelines provide no formal recommendation on when to check LDL-C after PCI.”

The meta-analysis followed a total of 4050 patients with diabetes and stable CAD from the three randomized trials, those with evaluable baseline and follow-up LDL-C measurements, for a median of 4 years after the 1-year LDL-C assessment. At that time, at least 90% of patients in each of the trials had statin prescriptions, the group reported.

At one year, 34.5% of the total cohort had an LDL-C <70 mg/dL; their mean was 55.8 mg/dL.

And 42.2% had an LDL-C from 70 mg/dL to <100 mg/dL; their mean was 83.4 mg/dL. Compared with patients with an LDL-C <70 mg/dL, their adjusted hazard ratio for the composite endpoint was not elevated at 1.07 (95% CI, 0.86-1.32, P = .54).

Finally, 23.2% had an LDL-C ≥100 mg/dL; the mean was 123.0 mg/dL. Compared with the group with the lowest 1-year LDL-C, their adjusted HR for MACCE was increased at 1.46 (95% CI, 1.15 - 1.85, P = .002).

That HR among the 42.3% of patients in the PCI cohort, compared with the 33.3% assigned to meds only, climbed significantly only among those in the lowest 1-year LDL-C stratum: HR, 0.61 (95% CI, 0.40-0.91, P = .016). Corresponding HRs in the mid-range and highest 1-year LDL strata were close to unity and nonsignificant at P = .71 and P = .98, respectively.

On the other hand, the 24.4% of patients assigned to CABG showed better MACCE outcomes than those in the meds-only group across all three 1-year LDL-C strata.

The risk of MACCE wasn’t significantly altered by CABG, compared with PCI among patients achieving a 1-year LDL-C less than 70 mg/dL. However, it fell by about one-half for CABG vs. PCI in both the mid-range and highest 1-year LDL-C strata, P = .003 and P = .022, respectively.

Dr. Bangalore said he’s entirely behind the results of the study’s comparison of PCI and CABG. “It’s exactly the hypothesis that I’ve been putting forward, that if you want to achieve results as good as CABG, do PCI with aggressive medical therapy.” That means second-generation drug-eluting stents for the target lesions, “and aggressive medical therapy to address all of the nontarget lesions, specifically in diabetics.”

It’s possible, Dr. Lloyd-Jones said, that there is “no longer a dichotomy between revascularization strategies,” with respect to clinical outcomes, in such patients who maintain an LDL less than 70 mg/dL, as the study suggests.

“But I wonder, if it had continued for another 4 years of follow-up, whether we would see the CABG patients start to have more events,” such that the CABG advantage goes away at higher LDL-C levels, he proposed.

Or, Dr. Lloyd-Jones speculated, if all patients had achieved LDL-C below 70 mg/dL, “would there be such a difference between the PCI and CABG groups? My bet would be that it would be small or abolished.”

Dr. Farkouh discloses receiving research grants from Amgen, Novo Nordisk, and Novartis. Disclosures for the other study authors can be found with the original article. Editorialist Dr. Navarese discloses receiving consulting fees or honoraria from Abbott, AstraZeneca, Amgen, Bayer, Sanofi, and Pfizer; and grants from Abbott and Amgen. Dr. Lloyd-Jones has disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

In order for percutaneous coronary intervention (PCI) to shine, compared with meds alone in patients with type-2 diabetes and stable coronary disease (CAD), it needs help from aggressive control of LDL cholesterol (LDL-C) levels, suggests a patient-level meta-analysis of three major randomized trials.

Performing PCI in such patients with diabetes conferred further benefit over optimal medical therapy (OMT) for major adverse cardiac or cerebrovascular events (MACCE) only among those whose LDL-C levels had been pushed below the guidelines-specified threshold of 70 mg/dL within 1 year.

At that level of LDL-C control, PCI, compared with the meds-alone strategy, was followed by a nearly 40% drop in 4-year risk for the composite endpoint, which consisted of death from any cause or nonfatal myocardial infarction (MI) or stroke.

Also for patients reaching a 1-year LDL-C of <70 mg/dL, the risk of MACCE was similar for those who had been assigned to coronary bypass surgery (CABG), compared with PCI. But that risk was significantly lower for the CABG group among those reaching LDL-C levels above that threshold.

“The strategy of revascularization with the LDL lowering, that’s the combination that seems to be a winner” in such patients with diabetes and stable CAD, lead author Michael E. Farkouh, MD, MSc, said in an interview.

If their LDL-C “stays above 70 mg/dL, they don’t really enjoy any benefit of PCI. It’s a message to our interventional community to really drive that LDL down,” said Dr. Farkouh, of the University of Toronto. “Not only with statins, but perhaps with PCSK9 inhibitors, ezetimibe, and other therapies to lower that LDL-C.”

The analysis, published Nov. 2 in the Journal of the American College of Cardiology, pooled more than 4,000 patients with diabetes and stable CAD randomized in the BARI 2D, FREEDOM, and COURAGE trials.

The new study adds a twist to an ongoing theme throughout some meta-analyses and clinical trials like ISCHEMIA since the results of COURAGE were unveiled 13 years ago. The latter trial famously saw no significant difference in death, MI, or stroke in patients with stable CAD assigned to OMT with or without PCI. That set off years of controversy about the relative merits of the revascularization and meds-only strategies in stable CAD that persists today.

But, Dr. Farkouh proposed, whether PCI improves clinical outcomes, compared with meds alone, at least in patients with diabetes, may be tied to the success of LDL-C-lowering therapies in reaching that goal, which in the current study was below 70 mg/dL.

“In this analysis of pooled data from the three major trials, we demonstrate that attaining that level of LDL-C at 1 year portends a better outcome for PCI” in patients with diabetes and stable CAD, he said.

The findings “probably need to be studied further, but it is compelling to think that if we can drive the LDL-C down by one year after the procedure, we have better outcomes with PCI,” compared with a meds-only strategy in patients with diabetes and stable CAD. “That really vindicates a lot of those who believe in PCI,” Dr. Farkouh said.

“What’s surprising to me is, if the patient has an LDL less than 70, why is it that there is a benefit of PCI, compared to medical therapy alone? Because they’re already so aggressively managed, you would think there shouldn’t be a benefit,” Sripal Bangalore, MD, MHA, New York University, said in an interview. “For me, that part is difficult to understand.”

The finding somewhat contradicts the results of ISCHEMIA, in which OMT – including LDL-C-lowering therapy – was considered more aggressive than usually managed in practice, Bangalore said. Yet the trial saw no outcomes difference between PCI and the more conservative approach, leading some to speculate that PCI may be a better choice when, for whatever reason, medical therapy isn’t optimal.

The observed superiority of PCI over meds-only at the lowest LDL-C levels is, according to Dr. Banagalore, “more likely because of residual confounding, given the fact that they’re combining three different trials, which are aimed to address different sets of questions.” He was an investigator with the FREEDOM and ISCHEMIA trials but isn’t associated with the current report.

The main message from this observational analysis is that “of course, we want to get the LDL as low as possible in these patients with demonstrated cardiovascular disease and diabetes,” Donald M. Lloyd-Jones, MD, ScM, Northwestern University, Chicago, said in an interview. “Every one of these patients should be shooting for as low an LDL as possible.”

Regardless of revascularization strategy, he said, “we have to get people on a high-intensity statin, or at least their maximally targeted dose, and have a careful and thoughtful conversation about whether they need additional lowering with, perhaps, ezetimibe, if they’re not below the thresholds we’d like to see them at, in this case, 70 mg/dL.”

Still, the current findings that the relative effects of PCI and CABG in these patients may vary by degree of LDL-C reduction “are interesting, but would have to be tested a little bit more directly,” said Dr. Lloyd-Jones, who is not affiliated with the analysis.

An accompanying editorial, which also acknowledges the study’s limitations, says its results “are relevant for clinical practice and may pave the way toward the generation of novel personalized medicine models that can optimize care of patients with type-2 diabetes.” 

They “support the concept of an individualized treatment strategy that accounts for a patient’s LDL-C level to estimate clinical outcomes and expected treatment effects after therapeutic interventions,” say the authors, led by Eliano P. Navarese, MD, PhD, Nicolaus Copernicus University, Bydgoszcz, Poland.

“For daily practice, these results also underscore the importance of follow-up LDL-C measurements, both as a risk stratifier and as an indicator for therapy adjustments,” they write, noting that “current guidelines provide no formal recommendation on when to check LDL-C after PCI.”

The meta-analysis followed a total of 4050 patients with diabetes and stable CAD from the three randomized trials, those with evaluable baseline and follow-up LDL-C measurements, for a median of 4 years after the 1-year LDL-C assessment. At that time, at least 90% of patients in each of the trials had statin prescriptions, the group reported.

At one year, 34.5% of the total cohort had an LDL-C <70 mg/dL; their mean was 55.8 mg/dL.

And 42.2% had an LDL-C from 70 mg/dL to <100 mg/dL; their mean was 83.4 mg/dL. Compared with patients with an LDL-C <70 mg/dL, their adjusted hazard ratio for the composite endpoint was not elevated at 1.07 (95% CI, 0.86-1.32, P = .54).

Finally, 23.2% had an LDL-C ≥100 mg/dL; the mean was 123.0 mg/dL. Compared with the group with the lowest 1-year LDL-C, their adjusted HR for MACCE was increased at 1.46 (95% CI, 1.15 - 1.85, P = .002).

That HR among the 42.3% of patients in the PCI cohort, compared with the 33.3% assigned to meds only, climbed significantly only among those in the lowest 1-year LDL-C stratum: HR, 0.61 (95% CI, 0.40-0.91, P = .016). Corresponding HRs in the mid-range and highest 1-year LDL strata were close to unity and nonsignificant at P = .71 and P = .98, respectively.

On the other hand, the 24.4% of patients assigned to CABG showed better MACCE outcomes than those in the meds-only group across all three 1-year LDL-C strata.

The risk of MACCE wasn’t significantly altered by CABG, compared with PCI among patients achieving a 1-year LDL-C less than 70 mg/dL. However, it fell by about one-half for CABG vs. PCI in both the mid-range and highest 1-year LDL-C strata, P = .003 and P = .022, respectively.

Dr. Bangalore said he’s entirely behind the results of the study’s comparison of PCI and CABG. “It’s exactly the hypothesis that I’ve been putting forward, that if you want to achieve results as good as CABG, do PCI with aggressive medical therapy.” That means second-generation drug-eluting stents for the target lesions, “and aggressive medical therapy to address all of the nontarget lesions, specifically in diabetics.”

It’s possible, Dr. Lloyd-Jones said, that there is “no longer a dichotomy between revascularization strategies,” with respect to clinical outcomes, in such patients who maintain an LDL less than 70 mg/dL, as the study suggests.

“But I wonder, if it had continued for another 4 years of follow-up, whether we would see the CABG patients start to have more events,” such that the CABG advantage goes away at higher LDL-C levels, he proposed.

Or, Dr. Lloyd-Jones speculated, if all patients had achieved LDL-C below 70 mg/dL, “would there be such a difference between the PCI and CABG groups? My bet would be that it would be small or abolished.”

Dr. Farkouh discloses receiving research grants from Amgen, Novo Nordisk, and Novartis. Disclosures for the other study authors can be found with the original article. Editorialist Dr. Navarese discloses receiving consulting fees or honoraria from Abbott, AstraZeneca, Amgen, Bayer, Sanofi, and Pfizer; and grants from Abbott and Amgen. Dr. Lloyd-Jones has disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

In order for percutaneous coronary intervention (PCI) to shine, compared with meds alone in patients with type-2 diabetes and stable coronary disease (CAD), it needs help from aggressive control of LDL cholesterol (LDL-C) levels, suggests a patient-level meta-analysis of three major randomized trials.

Performing PCI in such patients with diabetes conferred further benefit over optimal medical therapy (OMT) for major adverse cardiac or cerebrovascular events (MACCE) only among those whose LDL-C levels had been pushed below the guidelines-specified threshold of 70 mg/dL within 1 year.

At that level of LDL-C control, PCI, compared with the meds-alone strategy, was followed by a nearly 40% drop in 4-year risk for the composite endpoint, which consisted of death from any cause or nonfatal myocardial infarction (MI) or stroke.

Also for patients reaching a 1-year LDL-C of <70 mg/dL, the risk of MACCE was similar for those who had been assigned to coronary bypass surgery (CABG), compared with PCI. But that risk was significantly lower for the CABG group among those reaching LDL-C levels above that threshold.

“The strategy of revascularization with the LDL lowering, that’s the combination that seems to be a winner” in such patients with diabetes and stable CAD, lead author Michael E. Farkouh, MD, MSc, said in an interview.

If their LDL-C “stays above 70 mg/dL, they don’t really enjoy any benefit of PCI. It’s a message to our interventional community to really drive that LDL down,” said Dr. Farkouh, of the University of Toronto. “Not only with statins, but perhaps with PCSK9 inhibitors, ezetimibe, and other therapies to lower that LDL-C.”

The analysis, published Nov. 2 in the Journal of the American College of Cardiology, pooled more than 4,000 patients with diabetes and stable CAD randomized in the BARI 2D, FREEDOM, and COURAGE trials.

The new study adds a twist to an ongoing theme throughout some meta-analyses and clinical trials like ISCHEMIA since the results of COURAGE were unveiled 13 years ago. The latter trial famously saw no significant difference in death, MI, or stroke in patients with stable CAD assigned to OMT with or without PCI. That set off years of controversy about the relative merits of the revascularization and meds-only strategies in stable CAD that persists today.

But, Dr. Farkouh proposed, whether PCI improves clinical outcomes, compared with meds alone, at least in patients with diabetes, may be tied to the success of LDL-C-lowering therapies in reaching that goal, which in the current study was below 70 mg/dL.

“In this analysis of pooled data from the three major trials, we demonstrate that attaining that level of LDL-C at 1 year portends a better outcome for PCI” in patients with diabetes and stable CAD, he said.

The findings “probably need to be studied further, but it is compelling to think that if we can drive the LDL-C down by one year after the procedure, we have better outcomes with PCI,” compared with a meds-only strategy in patients with diabetes and stable CAD. “That really vindicates a lot of those who believe in PCI,” Dr. Farkouh said.

“What’s surprising to me is, if the patient has an LDL less than 70, why is it that there is a benefit of PCI, compared to medical therapy alone? Because they’re already so aggressively managed, you would think there shouldn’t be a benefit,” Sripal Bangalore, MD, MHA, New York University, said in an interview. “For me, that part is difficult to understand.”

The finding somewhat contradicts the results of ISCHEMIA, in which OMT – including LDL-C-lowering therapy – was considered more aggressive than usually managed in practice, Bangalore said. Yet the trial saw no outcomes difference between PCI and the more conservative approach, leading some to speculate that PCI may be a better choice when, for whatever reason, medical therapy isn’t optimal.

The observed superiority of PCI over meds-only at the lowest LDL-C levels is, according to Dr. Banagalore, “more likely because of residual confounding, given the fact that they’re combining three different trials, which are aimed to address different sets of questions.” He was an investigator with the FREEDOM and ISCHEMIA trials but isn’t associated with the current report.

The main message from this observational analysis is that “of course, we want to get the LDL as low as possible in these patients with demonstrated cardiovascular disease and diabetes,” Donald M. Lloyd-Jones, MD, ScM, Northwestern University, Chicago, said in an interview. “Every one of these patients should be shooting for as low an LDL as possible.”

Regardless of revascularization strategy, he said, “we have to get people on a high-intensity statin, or at least their maximally targeted dose, and have a careful and thoughtful conversation about whether they need additional lowering with, perhaps, ezetimibe, if they’re not below the thresholds we’d like to see them at, in this case, 70 mg/dL.”

Still, the current findings that the relative effects of PCI and CABG in these patients may vary by degree of LDL-C reduction “are interesting, but would have to be tested a little bit more directly,” said Dr. Lloyd-Jones, who is not affiliated with the analysis.

An accompanying editorial, which also acknowledges the study’s limitations, says its results “are relevant for clinical practice and may pave the way toward the generation of novel personalized medicine models that can optimize care of patients with type-2 diabetes.” 

They “support the concept of an individualized treatment strategy that accounts for a patient’s LDL-C level to estimate clinical outcomes and expected treatment effects after therapeutic interventions,” say the authors, led by Eliano P. Navarese, MD, PhD, Nicolaus Copernicus University, Bydgoszcz, Poland.

“For daily practice, these results also underscore the importance of follow-up LDL-C measurements, both as a risk stratifier and as an indicator for therapy adjustments,” they write, noting that “current guidelines provide no formal recommendation on when to check LDL-C after PCI.”

The meta-analysis followed a total of 4050 patients with diabetes and stable CAD from the three randomized trials, those with evaluable baseline and follow-up LDL-C measurements, for a median of 4 years after the 1-year LDL-C assessment. At that time, at least 90% of patients in each of the trials had statin prescriptions, the group reported.

At one year, 34.5% of the total cohort had an LDL-C <70 mg/dL; their mean was 55.8 mg/dL.

And 42.2% had an LDL-C from 70 mg/dL to <100 mg/dL; their mean was 83.4 mg/dL. Compared with patients with an LDL-C <70 mg/dL, their adjusted hazard ratio for the composite endpoint was not elevated at 1.07 (95% CI, 0.86-1.32, P = .54).

Finally, 23.2% had an LDL-C ≥100 mg/dL; the mean was 123.0 mg/dL. Compared with the group with the lowest 1-year LDL-C, their adjusted HR for MACCE was increased at 1.46 (95% CI, 1.15 - 1.85, P = .002).

That HR among the 42.3% of patients in the PCI cohort, compared with the 33.3% assigned to meds only, climbed significantly only among those in the lowest 1-year LDL-C stratum: HR, 0.61 (95% CI, 0.40-0.91, P = .016). Corresponding HRs in the mid-range and highest 1-year LDL strata were close to unity and nonsignificant at P = .71 and P = .98, respectively.

On the other hand, the 24.4% of patients assigned to CABG showed better MACCE outcomes than those in the meds-only group across all three 1-year LDL-C strata.

The risk of MACCE wasn’t significantly altered by CABG, compared with PCI among patients achieving a 1-year LDL-C less than 70 mg/dL. However, it fell by about one-half for CABG vs. PCI in both the mid-range and highest 1-year LDL-C strata, P = .003 and P = .022, respectively.

Dr. Bangalore said he’s entirely behind the results of the study’s comparison of PCI and CABG. “It’s exactly the hypothesis that I’ve been putting forward, that if you want to achieve results as good as CABG, do PCI with aggressive medical therapy.” That means second-generation drug-eluting stents for the target lesions, “and aggressive medical therapy to address all of the nontarget lesions, specifically in diabetics.”

It’s possible, Dr. Lloyd-Jones said, that there is “no longer a dichotomy between revascularization strategies,” with respect to clinical outcomes, in such patients who maintain an LDL less than 70 mg/dL, as the study suggests.

“But I wonder, if it had continued for another 4 years of follow-up, whether we would see the CABG patients start to have more events,” such that the CABG advantage goes away at higher LDL-C levels, he proposed.

Or, Dr. Lloyd-Jones speculated, if all patients had achieved LDL-C below 70 mg/dL, “would there be such a difference between the PCI and CABG groups? My bet would be that it would be small or abolished.”

Dr. Farkouh discloses receiving research grants from Amgen, Novo Nordisk, and Novartis. Disclosures for the other study authors can be found with the original article. Editorialist Dr. Navarese discloses receiving consulting fees or honoraria from Abbott, AstraZeneca, Amgen, Bayer, Sanofi, and Pfizer; and grants from Abbott and Amgen. Dr. Lloyd-Jones has disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

Patients receiving even top-notch hospital care for heart failure (HF) are, once discharged to home, at higher short-term risk of another HF hospitalization if home is in a socioeconomically deprived neighborhood. That helps explain why Blacks in the United States have a much higher 30-day HF readmission risk than Whites, a disparity that only worsens with the level of neighborhood deprivation, a new analysis suggests.

Some systemic and entrenched socioeconomic inequities that health care providers have little sway over, and which disproportionately affect Black individuals, are independent and robust predictors of worsened HF outcomes, Alanna A. Morris, MD, MSc, Emory University, Atlanta, said during her presentation at the virtual annual scientific meeting of the Heart Failure Society of America.

In a retrospective cohort study, Blacks had a 45% higher risk of 30-day readmission than Whites (P < .001) independent of cardiovascular risk factors, clinical history, comorbidities, type and location of hospital, and type of third-party payer coverage. The analysis included more than 30,000 patients with at least one HF hospitalization at centers in a major metropolitan health system.

The racial disparity widened with worsening socioeconomic deprivation of patients’ residential neighborhoods, that is, with rising quartiles of neighborhood scores on the Social Deprivation Index (SDI).

The SDI, based on U.S. census data, incorporates seven socioeconomic criteria, including household income, education level, employment, and prevalence of rented housing and households that are without a car, single parent, or overcrowded.

There was a 4–percentage point gap in adjusted 30-day readmission rate between Blacks and Whites in the lowest quartile that widened to more than 8 points by the third quartile; the disparity in both the second and fourth quartiles was the same, at about 5.5 percentage points.

A remaining question, Dr. Morris said in an interview, is why the outcomes disparity between Blacks and Whites peaks in the third SDI quartile but drops a bit in the fourth quartile representing the most severe neighborhood deprivation.

“Our hypothesis is that when you look at patients who are the poorest, who live in the most deprived neighborhoods, race may be less of a factor,” she said. Socioeconomic deprivation may have similar consequences for everyone “regardless of race, ethnicity, gender, or other demographic characteristics if you live in a neighborhood that’s highly deprived.”

Based on the current study, “it does appear that increased heart failure incident rates are related to living in deprived neighborhoods, and it raises important clinical and public health concerns that must be addressed,” Keith C. Ferdinand, MD, Tulane University, New Orleans, said as invited discussant after the presentation from Dr. Morris.

“These findings could serve as an aid to policy makers, going forward, in terms of allocating resources for primary health care,” he said. “And it’s important looking at these data and other [data] that we target heart failure patients who reside in deprived neighborhoods before, during, and [after] hospitalization.”

Dr. Morris agreed that policy makers are in a better position to attack the racial disparity in HF readmission rates identified in the study. “This is not a problem that can be fixed within the health care system.”

If the reported interpretation is correct, it could add a twist to the public health care debate in the United States, observed session moderator Mandeep R. Mehra, MD, Brigham and Woman’s Hospital in Boston.

That debate, he noted, has often focused on insurability, access to coverage, and the merits or shortcomings of a single-payer system. Yet the study suggests outcomes disparities stemming from neighborhood deprivation will not be corrected by improved access to health insurance, a conclusion he finds “startling,” Dr. Mehra said in an interview.

Some proposed explanations for the disparities by race blame unequal access to health care and or variable health insurance coverage, Dr. Morris observed in an interview. But “that may not fully explain the increased risk that we see.”

Black patients followed at Emory University’s advanced HF clinic still have a higher risk of rehospitalization than Whites. “These are patients who have insurance, who are followed by advanced heart failure providers, who are on equal amounts of guideline-recommended medical therapy – and you still see about a 50% higher risk of rehospitalization,” Dr. Morris said, citing data that isn’t part of the current analysis.

“We can say that these patients are certainly able to access care, because they are able to access our emergency room and be taken care of within the hospital setting,” he said. The study controlled for whether health coverage was by private insurance, Medicare, or Medicaid.

Instead, the current analysis points to socioeconomic and environmental factors as a major source of the disparity in 30-day readmissions, Dr. Morris said.

“When patients are discharged from our healthcare systems, they still go back into environments where they don’t have the same resources as patients who live in higher-SDI neighborhoods,” she explained.

For example, “we tell them to eat low-sodium [foods], exercise, eat fresh fruits and vegetables, take their medicines, but the reality is that certain neighborhoods within the United States – and this is much more true for Blacks – make it very difficult to follow those self-care recommendations.”

The analysis included 16,147 Black patients and 14,483 White patients hospitalized with HF within the Emory Healthcare system at least once from 2010-2018, Dr. Morris reported. Compared with Whites, Blacks were younger (63.5 vs 69.1 years) and less likely to be 65 or older (48.9% vs. 66.5%); more likely to be women (53.5% vs. 42.2%), more likely to reside in deprived census tracts and to have diabetes, hypertension, or chronic kidney disease; and had higher comorbidity scores.

In all, 20.6% of Black and 13.5% of White patients were readmitted for HF within 30 days of discharge, for an unadjusted risk ratio of 1.52 (95% CI, 1.44-1.61).

The RR hardly budged, 1.45 (95% CI, 1.37-1.54, P < .001), after adjustment for age, sex, type of insurance, type of HF, vital signs and laboratory values, medical history (diabetes, hypertension, atrial fibrillation, coronary disease, chronic kidney disease, and chronic pulmonary disease), Charlson Comorbidity Index, discharging medical specialty, and hospital location.

The excess in 30-day HF readmissions for Black, compared with White patients climbed from the first to the third neighborhood SDI quartile, the disparity peaking at 8.2 absolute percentage points.

A major criticism of the Hospital Readmissions Reduction Program component of the Affordable Care Act, Dr. Morris said in a Q&A discussion after her presentation, is that it can hold hospitals “responsible for structural inequalities that exist beyond the health care system,” including neighborhood deprivation.

“But public policy makers have to realize that there are certain patients we take care of who don’t have the resources to carry out the therapeutic lifestyle changes that will allow them to live healthy.”

The HRRP’s 30-day HF readmission metric that steers reimbursement “is penalizing health care systems across the United States” with its premise that hospital performance can be measured by 30-day HF readmission rates, Dr. Morris said in an interview.

“The reality is that some of these patients are going to a postdischarge environment that is inherently high risk, and that many of them are going to come back to us within 30 days,” she said. “We would like to make sure that we don’t put excess penalties on health care systems that take care of disproportionate numbers of African Americans in neighborhoods that have fewer resources.”

Dr. Morris and Dr. Ferdinand have disclosed no relevant financial relationships. Dr. Mehra discloses consulting or serving on an advisory board for Abbott, Medtronic, Janssen, Leviticus, NupulseCV, FineHeart, Portola, Bayer, the Baim Institute for Clinical Research, and Mesoblast.

A version of this article originally appeared on Medscape.com.

Patients receiving even top-notch hospital care for heart failure (HF) are, once discharged to home, at higher short-term risk of another HF hospitalization if home is in a socioeconomically deprived neighborhood. That helps explain why Blacks in the United States have a much higher 30-day HF readmission risk than Whites, a disparity that only worsens with the level of neighborhood deprivation, a new analysis suggests.

Some systemic and entrenched socioeconomic inequities that health care providers have little sway over, and which disproportionately affect Black individuals, are independent and robust predictors of worsened HF outcomes, Alanna A. Morris, MD, MSc, Emory University, Atlanta, said during her presentation at the virtual annual scientific meeting of the Heart Failure Society of America.

In a retrospective cohort study, Blacks had a 45% higher risk of 30-day readmission than Whites (P < .001) independent of cardiovascular risk factors, clinical history, comorbidities, type and location of hospital, and type of third-party payer coverage. The analysis included more than 30,000 patients with at least one HF hospitalization at centers in a major metropolitan health system.

The racial disparity widened with worsening socioeconomic deprivation of patients’ residential neighborhoods, that is, with rising quartiles of neighborhood scores on the Social Deprivation Index (SDI).

The SDI, based on U.S. census data, incorporates seven socioeconomic criteria, including household income, education level, employment, and prevalence of rented housing and households that are without a car, single parent, or overcrowded.

There was a 4–percentage point gap in adjusted 30-day readmission rate between Blacks and Whites in the lowest quartile that widened to more than 8 points by the third quartile; the disparity in both the second and fourth quartiles was the same, at about 5.5 percentage points.

A remaining question, Dr. Morris said in an interview, is why the outcomes disparity between Blacks and Whites peaks in the third SDI quartile but drops a bit in the fourth quartile representing the most severe neighborhood deprivation.

“Our hypothesis is that when you look at patients who are the poorest, who live in the most deprived neighborhoods, race may be less of a factor,” she said. Socioeconomic deprivation may have similar consequences for everyone “regardless of race, ethnicity, gender, or other demographic characteristics if you live in a neighborhood that’s highly deprived.”

Based on the current study, “it does appear that increased heart failure incident rates are related to living in deprived neighborhoods, and it raises important clinical and public health concerns that must be addressed,” Keith C. Ferdinand, MD, Tulane University, New Orleans, said as invited discussant after the presentation from Dr. Morris.

“These findings could serve as an aid to policy makers, going forward, in terms of allocating resources for primary health care,” he said. “And it’s important looking at these data and other [data] that we target heart failure patients who reside in deprived neighborhoods before, during, and [after] hospitalization.”

Dr. Morris agreed that policy makers are in a better position to attack the racial disparity in HF readmission rates identified in the study. “This is not a problem that can be fixed within the health care system.”

If the reported interpretation is correct, it could add a twist to the public health care debate in the United States, observed session moderator Mandeep R. Mehra, MD, Brigham and Woman’s Hospital in Boston.

That debate, he noted, has often focused on insurability, access to coverage, and the merits or shortcomings of a single-payer system. Yet the study suggests outcomes disparities stemming from neighborhood deprivation will not be corrected by improved access to health insurance, a conclusion he finds “startling,” Dr. Mehra said in an interview.

Some proposed explanations for the disparities by race blame unequal access to health care and or variable health insurance coverage, Dr. Morris observed in an interview. But “that may not fully explain the increased risk that we see.”

Black patients followed at Emory University’s advanced HF clinic still have a higher risk of rehospitalization than Whites. “These are patients who have insurance, who are followed by advanced heart failure providers, who are on equal amounts of guideline-recommended medical therapy – and you still see about a 50% higher risk of rehospitalization,” Dr. Morris said, citing data that isn’t part of the current analysis.

“We can say that these patients are certainly able to access care, because they are able to access our emergency room and be taken care of within the hospital setting,” he said. The study controlled for whether health coverage was by private insurance, Medicare, or Medicaid.

Instead, the current analysis points to socioeconomic and environmental factors as a major source of the disparity in 30-day readmissions, Dr. Morris said.

“When patients are discharged from our healthcare systems, they still go back into environments where they don’t have the same resources as patients who live in higher-SDI neighborhoods,” she explained.

For example, “we tell them to eat low-sodium [foods], exercise, eat fresh fruits and vegetables, take their medicines, but the reality is that certain neighborhoods within the United States – and this is much more true for Blacks – make it very difficult to follow those self-care recommendations.”

The analysis included 16,147 Black patients and 14,483 White patients hospitalized with HF within the Emory Healthcare system at least once from 2010-2018, Dr. Morris reported. Compared with Whites, Blacks were younger (63.5 vs 69.1 years) and less likely to be 65 or older (48.9% vs. 66.5%); more likely to be women (53.5% vs. 42.2%), more likely to reside in deprived census tracts and to have diabetes, hypertension, or chronic kidney disease; and had higher comorbidity scores.

In all, 20.6% of Black and 13.5% of White patients were readmitted for HF within 30 days of discharge, for an unadjusted risk ratio of 1.52 (95% CI, 1.44-1.61).

The RR hardly budged, 1.45 (95% CI, 1.37-1.54, P < .001), after adjustment for age, sex, type of insurance, type of HF, vital signs and laboratory values, medical history (diabetes, hypertension, atrial fibrillation, coronary disease, chronic kidney disease, and chronic pulmonary disease), Charlson Comorbidity Index, discharging medical specialty, and hospital location.

The excess in 30-day HF readmissions for Black, compared with White patients climbed from the first to the third neighborhood SDI quartile, the disparity peaking at 8.2 absolute percentage points.

A major criticism of the Hospital Readmissions Reduction Program component of the Affordable Care Act, Dr. Morris said in a Q&A discussion after her presentation, is that it can hold hospitals “responsible for structural inequalities that exist beyond the health care system,” including neighborhood deprivation.

“But public policy makers have to realize that there are certain patients we take care of who don’t have the resources to carry out the therapeutic lifestyle changes that will allow them to live healthy.”

The HRRP’s 30-day HF readmission metric that steers reimbursement “is penalizing health care systems across the United States” with its premise that hospital performance can be measured by 30-day HF readmission rates, Dr. Morris said in an interview.

“The reality is that some of these patients are going to a postdischarge environment that is inherently high risk, and that many of them are going to come back to us within 30 days,” she said. “We would like to make sure that we don’t put excess penalties on health care systems that take care of disproportionate numbers of African Americans in neighborhoods that have fewer resources.”

Dr. Morris and Dr. Ferdinand have disclosed no relevant financial relationships. Dr. Mehra discloses consulting or serving on an advisory board for Abbott, Medtronic, Janssen, Leviticus, NupulseCV, FineHeart, Portola, Bayer, the Baim Institute for Clinical Research, and Mesoblast.

A version of this article originally appeared on Medscape.com.

Patients receiving even top-notch hospital care for heart failure (HF) are, once discharged to home, at higher short-term risk of another HF hospitalization if home is in a socioeconomically deprived neighborhood. That helps explain why Blacks in the United States have a much higher 30-day HF readmission risk than Whites, a disparity that only worsens with the level of neighborhood deprivation, a new analysis suggests.

Some systemic and entrenched socioeconomic inequities that health care providers have little sway over, and which disproportionately affect Black individuals, are independent and robust predictors of worsened HF outcomes, Alanna A. Morris, MD, MSc, Emory University, Atlanta, said during her presentation at the virtual annual scientific meeting of the Heart Failure Society of America.

In a retrospective cohort study, Blacks had a 45% higher risk of 30-day readmission than Whites (P < .001) independent of cardiovascular risk factors, clinical history, comorbidities, type and location of hospital, and type of third-party payer coverage. The analysis included more than 30,000 patients with at least one HF hospitalization at centers in a major metropolitan health system.

The racial disparity widened with worsening socioeconomic deprivation of patients’ residential neighborhoods, that is, with rising quartiles of neighborhood scores on the Social Deprivation Index (SDI).

The SDI, based on U.S. census data, incorporates seven socioeconomic criteria, including household income, education level, employment, and prevalence of rented housing and households that are without a car, single parent, or overcrowded.

There was a 4–percentage point gap in adjusted 30-day readmission rate between Blacks and Whites in the lowest quartile that widened to more than 8 points by the third quartile; the disparity in both the second and fourth quartiles was the same, at about 5.5 percentage points.

A remaining question, Dr. Morris said in an interview, is why the outcomes disparity between Blacks and Whites peaks in the third SDI quartile but drops a bit in the fourth quartile representing the most severe neighborhood deprivation.

“Our hypothesis is that when you look at patients who are the poorest, who live in the most deprived neighborhoods, race may be less of a factor,” she said. Socioeconomic deprivation may have similar consequences for everyone “regardless of race, ethnicity, gender, or other demographic characteristics if you live in a neighborhood that’s highly deprived.”

Based on the current study, “it does appear that increased heart failure incident rates are related to living in deprived neighborhoods, and it raises important clinical and public health concerns that must be addressed,” Keith C. Ferdinand, MD, Tulane University, New Orleans, said as invited discussant after the presentation from Dr. Morris.

“These findings could serve as an aid to policy makers, going forward, in terms of allocating resources for primary health care,” he said. “And it’s important looking at these data and other [data] that we target heart failure patients who reside in deprived neighborhoods before, during, and [after] hospitalization.”

Dr. Morris agreed that policy makers are in a better position to attack the racial disparity in HF readmission rates identified in the study. “This is not a problem that can be fixed within the health care system.”

If the reported interpretation is correct, it could add a twist to the public health care debate in the United States, observed session moderator Mandeep R. Mehra, MD, Brigham and Woman’s Hospital in Boston.

That debate, he noted, has often focused on insurability, access to coverage, and the merits or shortcomings of a single-payer system. Yet the study suggests outcomes disparities stemming from neighborhood deprivation will not be corrected by improved access to health insurance, a conclusion he finds “startling,” Dr. Mehra said in an interview.

Some proposed explanations for the disparities by race blame unequal access to health care and or variable health insurance coverage, Dr. Morris observed in an interview. But “that may not fully explain the increased risk that we see.”

Black patients followed at Emory University’s advanced HF clinic still have a higher risk of rehospitalization than Whites. “These are patients who have insurance, who are followed by advanced heart failure providers, who are on equal amounts of guideline-recommended medical therapy – and you still see about a 50% higher risk of rehospitalization,” Dr. Morris said, citing data that isn’t part of the current analysis.

“We can say that these patients are certainly able to access care, because they are able to access our emergency room and be taken care of within the hospital setting,” he said. The study controlled for whether health coverage was by private insurance, Medicare, or Medicaid.

Instead, the current analysis points to socioeconomic and environmental factors as a major source of the disparity in 30-day readmissions, Dr. Morris said.

“When patients are discharged from our healthcare systems, they still go back into environments where they don’t have the same resources as patients who live in higher-SDI neighborhoods,” she explained.

For example, “we tell them to eat low-sodium [foods], exercise, eat fresh fruits and vegetables, take their medicines, but the reality is that certain neighborhoods within the United States – and this is much more true for Blacks – make it very difficult to follow those self-care recommendations.”

The analysis included 16,147 Black patients and 14,483 White patients hospitalized with HF within the Emory Healthcare system at least once from 2010-2018, Dr. Morris reported. Compared with Whites, Blacks were younger (63.5 vs 69.1 years) and less likely to be 65 or older (48.9% vs. 66.5%); more likely to be women (53.5% vs. 42.2%), more likely to reside in deprived census tracts and to have diabetes, hypertension, or chronic kidney disease; and had higher comorbidity scores.

In all, 20.6% of Black and 13.5% of White patients were readmitted for HF within 30 days of discharge, for an unadjusted risk ratio of 1.52 (95% CI, 1.44-1.61).

The RR hardly budged, 1.45 (95% CI, 1.37-1.54, P < .001), after adjustment for age, sex, type of insurance, type of HF, vital signs and laboratory values, medical history (diabetes, hypertension, atrial fibrillation, coronary disease, chronic kidney disease, and chronic pulmonary disease), Charlson Comorbidity Index, discharging medical specialty, and hospital location.

The excess in 30-day HF readmissions for Black, compared with White patients climbed from the first to the third neighborhood SDI quartile, the disparity peaking at 8.2 absolute percentage points.

A major criticism of the Hospital Readmissions Reduction Program component of the Affordable Care Act, Dr. Morris said in a Q&A discussion after her presentation, is that it can hold hospitals “responsible for structural inequalities that exist beyond the health care system,” including neighborhood deprivation.

“But public policy makers have to realize that there are certain patients we take care of who don’t have the resources to carry out the therapeutic lifestyle changes that will allow them to live healthy.”

The HRRP’s 30-day HF readmission metric that steers reimbursement “is penalizing health care systems across the United States” with its premise that hospital performance can be measured by 30-day HF readmission rates, Dr. Morris said in an interview.

“The reality is that some of these patients are going to a postdischarge environment that is inherently high risk, and that many of them are going to come back to us within 30 days,” she said. “We would like to make sure that we don’t put excess penalties on health care systems that take care of disproportionate numbers of African Americans in neighborhoods that have fewer resources.”

Dr. Morris and Dr. Ferdinand have disclosed no relevant financial relationships. Dr. Mehra discloses consulting or serving on an advisory board for Abbott, Medtronic, Janssen, Leviticus, NupulseCV, FineHeart, Portola, Bayer, the Baim Institute for Clinical Research, and Mesoblast.

A version of this article originally appeared on Medscape.com.